ACE insertion/deletion polymorphism (rs1799752) modifies the renoprotective effect of renin-angiotensin system blockade in patients with IgA nephropathy.

INTRODUCTION: Little is known about genetic predictors that modify the renoprotective effect of renin-angiotensin system (RAS) blockade in IgA nephropathy (IgAN). MATERIALS AND METHODS: The present multicenter retrospective observational study examined effect modification between RAS blockade and three RAS-related gene polymorphisms in 237 IgAN patients, including ACE I/D (rs1799752), AT1R A1166C (rs5186) and AGT T704C (rs699). RESULTS: During 9.9 ± 4.2 years of observation, 63 patients progressed to a 50% increase in serum creatinine level. Only ACE I/D predicted the outcome (ACE DD vs ID/II, hazard ratio 1.86 (95% confidence interval 1.03, 3.33)) and modified the renoprotective effect of RAS blockade (p for interaction between ACE DD and RAS blockade = 0.087). RAS blockade suppressed progression in ACE DD patients but not in ID/II patients (ACE ID/II with RAS blockade as a reference; ID/II without RAS blockade 1.45 (0.72, 2.92); DD without RAS blockade 3.06 (1.39, 6.73); DD with RAS blockade 1.51 (0.54, 4.19)), which was ascertained in a model with the outcome of slope of estimated glomerular filtration rate (p = 0.045 for interaction). CONCLUSION: ACE I/D predicted the IgAN progression and the renoprotective effect of RAS blockade in IgAN patients whereas neither AT1R A1166C nor AGT T704C did.

Laparoscopic-assisted catheter insertion for continuous ambulatory peritoneal dialysis: A case report of simple technique for optimal placement.

A 40-year-old male underwent tube placement surgery for continuous ambulatory peritoneal dialysis (CAPD). A 2-cm skin incision was made, and the peritoneum was reflected enough to perform secure fixation. A swan-necked, double-felted silicone CAPD catheter was inserted, and the felt cuff was sutured to the peritoneum to avoid postoperative leakage. An adequate gradient for tube fixation to the abdominal wall was confirmed. The CAPD tube was passed through a subcutaneous tunnel. Aeroperitoneum was induced to confirm that there was no air leakage from the sites of CAPD insertion. Two trocars were placed, and we confirmed that the CAPD tube led to the rectovesical pouch. Tip position was reliably observed laparoscopically. Optimal patency of the CAPD tube was confirmed during surgery. Placement of CAPD catheters by laparoscopic-assisted surgery has clear advantages in simplicity, safety, flexibility, and certainty. Laparoscopic technique should be considered the first choice for CAPD tube insertion.

Hematogenous umbilical metastasis from colon cancer treated by palliative single-incision laparoscopic surgery.

Sister Mary Joseph's nodule (SMJN) is a rare umbilical nodule that develops secondary to metastatic cancer. Primary malignancies are located in the abdomen or pelvis. Patients with SMJN have a poor prognosis. An 83-year-old woman presented to our hospital with a 1-month history of a rapidly enlarging umbilical mass. Endoscopic findings revealed advanced transverse colon cancer. computer tomography and fluorodeoxyglucose-positron emission tomography revealed tumors of the transverse colon, umbilicus, right inguinal lymph nodes, and left lung. The feeding arteries and drainage veins for the SMJN were the inferior epigastric vessels. Imaging findings of the left lung tumor allowed for identification of the primary lung cancer, and a diagnosis of advanced transverse colon cancer with SMJN and primary lung cancer was made. The patient underwent local resection of the SMNJ and subsequent single-site laparoscopic surgery involving right hemicolectomy and paracolic lymph node dissection. Intra-abdominal dissemination to the mesocolon was confirmed during surgery. Histopathologically, the transverse colon cancer was confirmed to be moderately differentiated tubular adenocarcinoma. We suspect that SMJN may occur via a hematogenous pathway. Although chemotherapy for colon cancer and thoracoscopic surgery for the primary lung cancer were scheduled, the patient and her family desired home hospice. Seven months after surgery, she died of rapidly growing lung cancer.

Association of nocturnal hypoxemia with progression of CKD.

BACKGROUND AND OBJECTIVES: Nocturnal hypoxemia is highly prevalent among patients with CKD. Nocturnal hypoxemia contributes to systemic inflammation, oxidative stress, endothelial cell dysfunction, and activation of the renin-angiotensin system, which are common pathologic mechanisms of CKD progression. This study investigated whether nocturnal hypoxemia is independently associated with CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This two-center retrospective cohort study included 161 patients with stages 3-4 CKD enrolled from January of 2009 to July of 2011 with a body mass index less than 25.0 kg/m(2). The 4% oxygen desaturation index, the number of events per hour in which oxygen saturation decreases by >4% during sleep, was measured, and the declining rate of the estimated GFR was followed over 1 year. The severity of nocturnal hypoxemia was categorized as none (oxygen desaturation index<5.0), mild (5.0≤oxygen desaturation index<15.0), or moderate to severe (15.0≤oxygen desaturation index). RESULTS: The mean estimated GFR of the total cohort at baseline was 31 ml/min per 1.73 m(2). Eighty patients (49.7%) were diagnosed with nocturnal hypoxemia; 64 patients were diagnosed with mild nocturnal hypoxemia, and 16 patients were diagnosed with moderate-to-severe nocturnal hypoxemia. The estimated GFR declined three- to fourfold faster in patients with moderate-to-severe nocturnal hypoxemia than patients with no or mild nocturnal hypoxemia (the mean values [95% confidence intervals] were -2.14 [-1.06 to -3.21], -3.02 [-1.31 to -4.74], and -8.59 [-2.00 to -15.2] ml/min per 1.73 m(2) per year in the no, mild, and moderate-to-severe nocturnal hypoxemia groups, respectively; P=0.003). Nocturnal hypoxemia remained a significant predictor of decline in estimated GFR after adjustment for various baseline clinical factors. CONCLUSIONS: In nonobese patients with CKD, nocturnal hypoxemia is an independent risk factor of a rapid decline in kidney function.

Angiotensin II receptor blockade reduces salt sensitivity of blood pressure through restoration of renal nitric oxide synthesis in patients with diabetic nephropathy.

INTRODUCTION: We have previously demonstrated the increased salt sensitivity of blood pressure (BP) in diabetic patients with early nephropathy. Here, we examined the effects of an angiotensin II receptor blocker (ARB) on salt sensitivity and renal oxidative stress or nitric oxide (NO) in those patients. PATIENTS AND METHODS: Type 2 diabetic patients with (n = 6) and without (n = 6) microalbuminuria were studied on a high-salt diet for one week and on a salt-restricted diet for one week. The study was repeated in the patients with microalbuminuria during treatment with an ARB, valsartan (80 mg/day). Salt sensitivity was assessed from the BP/sodium excretion curve. Urinary excretion rates of NOx, 8-hydroxy-2-deoxyguanosine as a marker of oxidative stress, and plasma tetrahydrobiopterin as a cofactor for NO synthase were measured. RESULTS: Compared with diabetic patients without microalbuminuria, patients with microalbuminuria showed greater salt sensitivity and lower urinary excretion of NOx. In the patients with microalbuminuria, treatment with valsartan reduced salt sensitivity in association with increased NOx excretion, reduced 8-hydroxy-2,-deoxyguanosine excretion, and increased plasma tetrahydrobiopterin levels. CONCLUSIONS: These data support the hypothesis that ARBs reduce the salt sensitivity of BP by decreasing renal oxidative stress and restoring NO activity in diabetic patients with microalbuminuria.

Serum hepcidin-25 levels predict the progression of renal anemia in patients with non-dialysis chronic kidney disease.

BACKGROUND: Hepcidin is associated with iron-restricted erythropoiesis. A previous cross-sectional study showed that serum hepcidin-25 levels are negatively associated with the hemoglobin concentration in non-dialysis chronic kidney disease (CKD) patients with sufficient iron stores. This longitudinal study aimed at ascertaining the association between hepcidin-25 levels and the progression of renal anemia. METHODS: We selected 335 non-dialysis CKD patients who showed hemoglobin concentrations >10 g/dL and who were not receiving erythropoiesis-stimulating agent (ESA) therapy, from among the subjects of our previous study, who had been recruited between February and June 2007 in a previous study. The primary outcome was the start of the ESA therapy or hemoglobin concentrations remaining below 10 g/dL for >3 months, by 31 December 2010. The patients were classified into high- and low-ferritin groups depending on their median ferritin levels. The Cox proportional hazard model with restricted cubic spline curve analysis was used to determine the association between hepcidin-25 levels and the outcome for each group. RESULTS: The hepcidin-25 level was a significant predictor both for the high-ferritin group (P = 0.04, linearity = 0.02) and for the low-ferritin group (P = 0.04, linearity P = 0.02). The spline curve for the high-ferritin group showed that higher hepcidin-25 levels had a high log-relative hazard. CONCLUSIONS: Higher hepcidin-25 levels predict the progression of anemia in non-dialysis CKD patients with sufficient iron stores, indicating the involvement of hepcidin in the progression of anemia in non-dialysis CKD patients.

Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease.

OBJECTIVE: There is now growing evidence that magnesium (Mg) deficiency is implicated in type 2 diabetes and its complications. However, it has not been fully elucidated whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in type 2 diabetic nephropathy. RESEARCH DESIGN AND METHODS: This retrospective cohort study included 455 chronic kidney disease (CKD) patients (144 with type 2 diabetic nephropathy and 311 with nondiabetic CKD) who were hospitalized at Osaka General Medical Center for a CKD educational program between April 2001 and December 2007. The primary outcome was progression to renal replacement therapy. Participants were categorized based on serum Mg level into Low-Mg (serum Mg level ≤1.8 mg/dL) and High-Mg (serum Mg level >1.8 mg/dL) groups with the previously published normal lower limit chosen as the cutoff point. RESULTS: Of the subjects with type 2 diabetic nephropathy, 102 progressed to ESRD during follow-up (median, 23 months). A multivariate Cox proportional hazards model showed that after adjustment for various demographic factors and laboratory data, the Low-Mg group had a 2.12-fold higher risk of ESRD than the High-Mg group (95% CI 1.28-3.51; P = 0.004). In contrast, 135 of the nondiabetic CKD subjects progressed to ESRD during follow-up (median, 44 months). No significant difference in outcome was found between the Low- and High-Mg groups of this population (adjusted hazard ratio, 1.15; 95% CI 0.70-1.90; P = 0.57). CONCLUSIONS: Hypomagnesemia is a novel predictor of ESRD in patients with type 2 diabetic nephropathy.

Tonsillectomy has beneficial effects on remission and progression of IgA nephropathy independent of steroid therapy.

BACKGROUND: Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to examine the efficacy of tonsillectomy on remission and progression of IgA nephropathy. METHODS: We conducted a single-center 7-year historical cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as disappearance of urine abnormalities at two consecutive visits, glomerular filtration rate (GFR) decline defined as 30% GFR decrease from baseline and GFR slope during the follow-up. RESULTS: Seventy of the 200 patients received tonsillectomy. Tonsillectomy was associated with increased incidence of clinical remission (P+0.01, log-rank test) and decreased incidence of GFR decline (P=0.01, log-rank test). After adjustment for age and gender, hazard ratios in tonsillectomy were 3.90 (95% confidence interval 2.46-6.18) for clinical remission and 0.14 (0.02-1.03) for GFR decline. After further adjustment for laboratory (baseline mean arterial pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion, endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin-angiotensin system inhibitors), similar results were obtained in each model. Even after exclusion of 69 steroid-treated patients, results did not change. GFR slopes in tonsillectomy and non-tonsillectomy groups were 0.60±3.65 and -1.64±2.59 mL/min/1.73 m2/year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P=0.01). CONCLUSION: Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration even in non-steroid-treated patients.

Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis.

PURPOSE: Low 25-hydroxyvitamin D (25D), increased levels of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were reported to be risk factors for mortality in chronic kidney disease (CKD). However, the independent associations of these factors with cardiovascular disease (CVD), the leading cause of death among CKD patients, remain unclear. Our purpose was to identify which of these factors predict incident CVD in CKD. METHODS: In this prospective cohort study, we enrolled 738 predialysis outpatients in the two nephrology departments. We employed Cox proportional hazards analyses to elucidate predictors of the endpoint, defined as fatal or non-fatal cardiovascular event requiring hospitalization. Multiple imputation was performed for missing values. RESULTS: Mean estimated glomerular filtration rate (eGFR) was 35 mL/min/1.73 m(2). During a median duration of 4.4 years, 86 patients developed the endpoint, of whom 62 patients achieved it before the initiation of dialysis. Multivariable analyses revealed that high serum intact FGF23 levels predicted the outcome preceding dialysis initiation (hazard ratio (HR) per lnFGF23 (SD), 1.64 (1.27-2.30)), while 25D, PTH, and bone-specific ALP did not. Adding FGF23 to the conventional model of age, sex, diabetes, prior CVD, pulse pressure, and eGFR, led to a net reclassification improvement of 6.87% (P=0.04). Not censoring the patients at the start of dialysis and continuing follow-up even after dialysis, FGF23 levels did not predict the outcome (HR, 1.16 (0.91-1.48)). Complete case analyses yielded similar results. CONCLUSIONS: Intact FGF23 levels in predialysis CKD predicted incident cardiovascular events requiring hospitalization before starting dialysis, but did not predict events during the entire follow-up period, including post dialysis initiation.

Combined use of vitamin D status and FGF23 for risk stratification of renal outcome.

BACKGROUND AND OBJECTIVES: Hyperphosphatemia, vitamin D deficiency, hyperparathyroidism, and high serum fibroblast growth factor 23 (FGF23) levels, when studied separately, were found to predict the progression of CKD. However, studies with simultaneous measurement of mineral bone disorder (MBD)-related factors were scarce. This study aimed to identify factors predicting renal outcome independent of other factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective cohort study of 738 Japanese predialysis outpatients in the nephrology departments of two hospitals. The outcome was defined as a doubling of serum creatinine or initiation of dialysis. RESULTS: Mean estimated GFR (eGFR) was 35 ml/min per 1.73 m(2). At enrollment, the increase in intact FGF23 with decreasing eGFR was the earliest among changes in MBD-related factors, followed by 1,25-dihydroxyvitamin D decrease, parathyroid hormone increase, and phosphate increase. During a median duration of 4.4 years, 213 patients reached the endpoint. In a multivariable Cox model, high FGF23 and low 25-hydroxyvitamin D (25D) levels were the only MBD-related factors associated with a higher risk of renal endpoint (adjusted hazard ratio [95% confidence interval] per unit change of log FGF23 and 10 ng/ml of 25D: 1.83 [1.28-2.61] and 0.61 [0.41-0.90], respectively). There was no significant interaction between 25D and FGF23 (P=0.11). Active vitamin D therapy, serum phosphate, 1,25-dihydroxyvitamin D, and parathyroid hormone levels were not related to the renal endpoint. Treating death as a competing risk or multiple imputation for missing values yielded similar results. CONCLUSIONS: Combined use of two markers is useful for the risk stratification of renal outcome.

Gene polymorphisms contributing to hypertension in immunoglobulin A nephropathy.

BACKGROUND: Hypertension, which is affected by genetic and environmental factors, is one of the major risk factors for chronic kidney disease. Identification of the genetic factor contributing to hypertension in patients with chronic kidney disease may potentially refine a therapeutic strategy. METHODS: In the present multicenter cross-sectional study, 240 patients were eligible (aged 15-50 years with urinary protein ≥0.25 g/day) out of 429 patients who were diagnosed as having immunoglobulin (Ig) A nephropathy (IgAN) by renal biopsy between 1990 and 2005 and enrolled in our previous study, PREDICT-IgAN. The outcome was hypertension defined as ≥140 and/or ≥90 mmHg of systolic and diastolic blood pressure and/or use of antihypertensives at renal biopsy. We assessed associations between hypertension and 28 polymorphisms with the frequency of minor genotype ≥10% among 100 atherosclerosis-related polymorphisms using the Chi-squared test in dominant and recessive models. We identified polymorphisms associated with hypertension in multivariate logistic regression models. RESULTS: Baseline characteristics: hypertension 36.3%. Among 28 polymorphisms, the Chi-squared test revealed that CD14 (-159CC vs CT/TT, P = 0.03) and ACE (DD vs DI/II, P = 0.03) were significantly associated with hypertension after Bonferroni correction. Multivariate logistic regression models revealed that CD14 -159CC [vs CT/TT, odds ratio (OR) 3.58 (95% confidence interval (CI) 1.66-7.63)] and ACE DD [vs DI/II, OR 4.41 (95% CI 1.80-10.8), P = 0.001] were independently associated with hypertension. CONCLUSIONS: CD14 C-159T and ACE I/D contributed to hypertension in patients with IgAN.

Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study.

BACKGROUND: Hepcidin is a central regulator of iron homeostasis. Increased hepcidin concentrations could cause iron-restricted erythropoiesis in chronic kidney disease (CKD)-associated anemia. This cross-sectional observational study was conducted to evaluate the association between hepcidin and CKD-associated anemia in non-dialysis CKD patients. METHODS: A total of 505 non-dialysis CKD patients not treated with parenteral iron were recruited, and serum hepcidin-25 levels were measured by liquid chromatography tandem mass spectrometry. Multiple linear regression analysis was used to examine the relationship between hepcidin and glomerular filtration rate (GFR) and the relationship between hemoglobin concentration and predictors including the hepcidin level. RESULTS: The median hepcidin level among the 505 CKD patients was 15.4 ng/mL (interquartile range, 5.5-33.6 ng/mL). Although hepcidin level significantly increased according to the CKD stage, multivariate analysis did not reveal an association of GFR with the hepcidin level. Hepcidin level was a significant predictor of hemoglobin concentration after the adjustment for confounders, and a significant interaction between hepcidin and ferritin was found. After stratifying at the median ferritin level, 91 ng/mL, we found a negative association between hepcidin level and hemoglobin in the high-ferritin group. A trend toward a negative association between hepcidin level and mean corpuscular volume was observed in the high-ferritin group. CONCLUSIONS: Serum hepcidin-25 levels were negatively associated with hemoglobin concentrations in non-dialysis CKD patients with sufficient iron stores. We found that ferritin modified the association between hepcidin level and hemoglobin concentration. In addition, our results confirmed that the serum hepcidin level is not associated with GFR.

Guideline-practice gap in the management of predialysis chronic kidney disease mineral bone disorder in Japan.

No study has reported the current status of the management of chronic kidney disease mineral bone disorder (CKD-MBD) in Japan. Using the Osaka Vitamin D Study in CKD (OVIDS-CKD), we examined the prevalence of patients with serum calcium, phosphate, parathyroid hormone (PTH), or 25-hydroxyvitamin D levels outside the target of KDOQI guidelines. Eighty-four percent of the patients had 25-hydroxyvitamin D <30 ng/mL. Significant determinants of poor vitamin D status were female gender, diabetes, high PTH, and high urinary protein (2+ or greater). The percentage of patients with intact PTH higher than the target was 8% in CKD stage 3a, while between 20-22% in stages 3b to 5. The patients indicated for ergocalciferol were 7, 18, and 19% in stages 3a, 3b, and 4, respectively, and those indicated for active vitamin D were 21% in stage 5. Since neither ergocalciferol nor cholecalciferol is available in 2011 in Japan, we have no choice but to prescribe alfacalcidol or calcitriol; however, the percent of patients receiving these drugs was only 1, 4, 8, and 14% in stages 3a, 3b, 4, and 5, respectively, indicating that PTH and vitamin D status are not well controlled in Japan. In contrast, more than 80% of the patients met the target of serum calcium and phosphate. Contrary to expectations, nearly 20% of the patients had hypophosphatemia in stage 3 and 5, possibly because of strict protein restriction. Given these results, nephrologists should consider prescribing active vitamin D, especially for females and patients with diabetes, massive proteinuria, or secondary hyperparathyroidism.

High prevalence of obstructive sleep apnea and its association with renal function among nondialysis chronic kidney disease patients in Japan: a cross-sectional study.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) affects one of five adults in the general population. Although a high prevalence of OSA has been reported among dialysis patients, the association between nondialysis chronic kidney disease (CKD) and OSA has not been fully investigated. This cross-sectional study aimed to investigate the prevalence of OSA among nondialysis CKD patients in Japan and the association between renal function and OSA. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Consecutive nondialysis CKD patients hospitalized mainly for CKD educational program, regardless of their sleep complaints, were enrolled. The diagnosis of OSA and its severity were measured using a type 3 portable monitor. RESULTS: Overall (n=100, 68.0% male, median age 66.5 years, body mass index [BMI] 23.1 kg/m(2), estimated GFR [eGFR] 28.5 ml/min per 1.73 m(2)), 65% were diagnosed as OSA: mild OSA (apnea-hypopnea index [AHI] 5.0 to 14.9) in 32%, moderate OSA (AHI 15.0 to 29.9) in 25%, and severe OSA (AHI ≥ 30.0) in 8%. Multivariate logistic regression analysis revealed that a 10-ml/min per 1.73 m(2) decrease in eGFR was associated with a 42% increased odds of OSA after adjustment for age, BMI, and diabetes mellitus. Moreover, in a generalized linear model, eGFR was inversely correlated with AHI after adjustment for covariates. CONCLUSIONS: This study demonstrated a high prevalence of OSA among nondialysis CKD patients in Japan and that the increased risk of OSA was significantly associated with decreased GFR among these patients. Further investigations are warranted to determine OSA's direct influence on cardiovascular disease.

Cigarette smoking and progression of IgA nephropathy.

BACKGROUND: Multiple community-based cohort studies of mainly middle-aged and elderly populations have shown that cigarette smoking is a risk factor for chronic kidney disease. However, little information is available about an effect of cigarette smoking on progression of primary kidney diseases, including immunoglobulin A (IgA) nephropathy. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 971 of 1,001 patients with a diagnosis of IgA nephropathy in 3 major nephrology centers in Osaka, Japan, between 1992 and 2005 who enrolled in the Study of Outcome and Practice Pattern of IgA Nephropathy (STOP-IgAN). PREDICTORS: Smoking status and number of cigarettes smoked at the time of diagnosis using kidney biopsy. Dose-dependent associations between cigarette smoking and outcomes were assessed in multivariate Cox proportional hazards models. Significantly different clinical characteristics between non-/past and current smokers were controlled for using propensity score-based adjustment, stratification, and matching. OUTCOMES: 50% increase in serum creatinine level as primary outcome. A composite outcome of a 100% increase in serum creatinine level or end-stage renal disease (ESRD) and ESRD alone as secondary outcomes. RESULTS: During the median 5.8 years (interquartile range, 2.6-10.2) of the observational period, 117 participants progressed to a 50% increase in serum creatinine level and 47 advanced to ESRD. Multivariate Cox proportional hazards models identified current smokers (HR, 2.03 [95% CI, 1.33-3.10] for primary outcome) and number of cigarettes at kidney biopsy (HR, 1.21 [95% CI, 1.06-1.39] per 10 cigarettes per day) as significant predictors of outcomes. Propensity score-based models confirmed these results. Tests for interaction showed that the association of current smoking with adverse outcomes was stronger in those with lower compared with higher estimated glomerular filtration rates. LIMITATION: Baseline smoking status was not verified using biochemical tests. Smoking status during the observational period was unavailable. CONCLUSIONS: Cigarette smoking, in a dose-dependent manner, was identified as a key prognostic factor in IgA nephropathy. Smoking cessation should be encouraged as part of the treatment for IgA nephropathy.

[Autopsy case of PR3-ANCA-associated vasculitis complicated with rectus muscle hematoma].

A 80-year-old man was admitted to our hospital because of coughing, hemosputum and dyspnea. As a chest X-ray showed infiltrates of the right lung, he was diagnosed as bacterial pneumonia and treated with antibiotics. However, after a few days, he exhibited hemoptysis and developed severe dyspnea, while laboratory findings showed rapid elevation of the serum creatinine level (5.55 mg dL). Computed tomography (CT) revealed large areas of ground glass opacity in the right lung, hence the hemoptysis was considered to be due to alveolar hemorrhage. As he had been diagnosed as chronic renal failure a few years before this admission and we also noticed that interstitial pneumonia with a slightly elevated level of C-reactive protein had existed from that time, ANCA-associated vasculitis was suspected to be the underlying pathogenesis. Accordingly, he was started on methylprednisolone pulse therapy and temporary hemodialysis resulted in improvement of dyspnea and renal function. PR3-ANCA was 12.4 EU, so he was diagnosed as PR3-ANCA-associated vasculitis. After a few days, he suddenly complained of abdominal pain, developing hypotension and anemia. Abdominal CT showed an irregular low-density mass in the right muscle, so he was diagnosed as rectus muscle hematoma. Surgery was performed and a massive hematoma was found in the rectus muscle without any ruptures of macroscopic vessels in the abdomen. Bleeding could not be stopped followed by multiple organ failure and the patient died four days postoperatively. Rectus muscle hematoma is an uncommon cause of acute abdomen, and has been reported in about 100 cases in Japan. It occurs because of a tear in epigastric vessels and is usually managed conservatively with a good prognosis, although hemodynamically unstable cases require surgery. To the best of the authors' knowledge, this is the first case of rectus muscle hematoma complicated with ANCA-associated vasculitis.

Serum 25-hydroxyvitamin D as an independent determinant of 1-84 PTH and bone mineral density in non-diabetic predialysis CKD patients.

The role of 25-hydroxyvitamin D [25(OH)D] and fibroblast growth factor-23 (FGF-23) in chronic kidney disease-mineral and bone disorder (CKD-MBD) remains elusive in predialysis CKD patients. From the fact that FGF-23 suppresses bone mineralization in vitro and that 1alpha-hydroxylase is present in parathyroid cells and osteoblasts, they may be associated with bone mass or serum parathyroid hormone (PTH) level. In this cross-sectional observational study, we investigated the potential associations of 25(OH)D or FGF-23 with 1-84 PTH and bone mineral density (BMD) in the femoral neck (FN) and lumbar spine (LS) of 325 non-diabetic patients. All patients had stages 3-5 CKD and had never been treated with bisphosphonate, estrogen, or vitamin D. We measured bone-specific alkaline phosphatase (bone ALP), intact FGF-23 and 1-84 PTH in a third generation assay, and performed a multiple regression analysis for 1-84 PTH and BMD Z-score. In our cohort, 80.1% had 25(OH)D levels less than 30 ng/mL, and 4.1% had levels less than 15 ng/mL. A univariate analysis indicated a negative association for 25(OH)D with 1-84 PTH and bone ALP. A multivariate analysis showed that the significant determinants for 1-84 PTH were 25(OH)D, estimated glomerular filtration rate (eGFR), corrected calcium, serum calcitriol and phosphate. Intriguingly, the three former parameters had negative associations with 1-84 PTH while calcitriol had a positive association. While further adjustment of FGF-23 extinguished the positive association of phosphate and 1-84 PTH, there was absolutely no increase in the R2. With regard to the BMD Z-score, 25(OH)D and the body mass index were the significant common independent positive determinants for both FN and LS, whereas bone ALP was the negative determinant even though there was no correlation noted for 1-84 PTH, calcitriol, or FGF-23 with BMD. In addition, eGFR positively contributed to the Z-score only in FN. Therefore, despite a positive correlation between 25(OH)D and calcitriol, their contribution to the CKD-MBD appears to be different. Since the significant associations for 25(OH)D with 1-84 PTH and BMD were independent of serum calcitriol and bone ALP, this might imply that 25(OH)D has a direct effect on the parathyroid gland and bone.

Tubulointerstitial nephritis and uveitis (TINU) syndrome caused by the Chinese herb "Goreisan".

A 58-year-old man was admitted to our hospital complaining of fever and arthralgia. His clinical course and marked ciliary hyperemia led us to suspect tubulointestinal nephritis and uveitis (TINU) syndrome, which was confirmed ophthalmologically and by renal biopsy. Results of a drug-induced lymphocyte-stimulating test were positive for the Chinese herb "Goreisan." This is the first case in which the use of "Goreisan" was causally related to TINU syndrome.

Evidence for abundant presence of chymase-positive mast cells in the kidneys of patients with immunoglobulin A nephropathy: effect of combination therapy with prednisolone and angiotensin II receptor blocker valsartan.

Several investigators have reported chymase-positive mast cells in tubulointerstitial damage. However, the significance of the presence of chymase in the pathophysiology of renal diseases is unclear. We investigated relationships among chymase, renal damage, and intra-renal circulation. The participant pool consisted of 52 patients with immunoglobulin A (IgA) nephropathy who underwent renal biopsy. Of these, 18 were examined before and 2 months after the initiation of treatment with prednisolone alone (n=9) or combined with the angiotensin II receptor blocker valsartan (n=9). Biopsied renal specimens were evaluated, and the degree of renal circulation (resistive index; RI) was calculated by measuring flow velocity using Doppler sonography. The number of chymase-positive mast cells as visualized by immunohistochemical staining correlated significantly with both tubulointerstitial damage (rho=0.69, p<0.001) and RI (r=0.52, p<0.001). Treatment with prednisolone combined with valsartan effectively decreased both chymase-positive mast cells and RI, displaying a significant correlation between these biomarkers (rho=0.85, p=0.016). However, no such effect was observed with prednisolone alone. The severity of tubulointerstitial damage and the degree of proteinuria were similar in both treatment groups throughout the study term. We concluded that the presence of chymase-positive mast cells and the associated decrease in renal circulation corresponded to disease progression in IgA nephropathy. Combination therapy using prednisolone and valsartan may lead to improvements in intra-renal circulation and to interference in the recruitment of chymase-positive mast cells.

Strict angiotensin blockade prevents the augmentation of intrarenal angiotensin II and podocyte abnormalities in type 2 diabetic rats with microalbuminuria.

OBJECTIVES: Beneficial effects of angiotensin II type 1 receptor blockers have been indicated for patients with diabetic nephropathy. We investigated the effects of an angiotensin II type 1 receptor blocker, telmisartan, on intrarenal angiotensin II levels and the progression of albuminuria or glomerular injury in type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats with microalbuminuria. METHODS AND RESULTS: Otsuka Long-Evans Tokushima Fatty rats were randomly treated with telmisartan (10 mg/kg/day, orally), hydralazine (25 mg/kg/day in drinking water) or vehicle from the initiation of albuminuria (13 weeks old). At this age, Otsuka Long-Evans Tokushima Fatty rats showed low but detectable albuminuria (1.0 +/- 0.1 mg/day) and higher systolic blood pressure, postprandial blood glucose and kidney angiotensin II levels than age-matched nondiabetic Long-Evans Tokushima Otsuka rats. At 35 weeks of age, vehicle-treated Otsuka Long-Evans Tokushima Fatty rats did not show apparent glomerular injury or tubulointerstitial fibrosis but did exhibit severe albuminuria (72.6 +/- 5.9 mg/day) and accumulation of cytoplasmic granules containing albumin in podocytes. Otsuka Long-Evans Tokushima Fatty rats also showed higher systolic blood pressure, postprandial blood glucose, collagen gene expression, desmin staining (a marker of podocyte injury) and angiotensin II levels than Long-Evans Tokushima Otsuka rats. Treatment with telmisartan did not affect postprandial blood glucose but decreased systolic blood pressure, collagen gene expression, desmin staining and angiotensin II levels. Telmisartan also prevented the development of albuminuria (0.6 +/- 0.1 mg/day at 35 weeks old) and accumulation of cytoplasmic granules. Hydralazine treatment resulted in a similar reduction in systolic blood pressure and partially attenuated the albuminuria (35.4 +/- 1.8 mg/day at 35 weeks old) but did not affect the other parameters. CONCLUSION: The present results suggest the contribution of augmented intrarenal angiotensin II levels to the initiation and progression of albuminuria as well as podocyte abnormalities in type 2 diabetic rats. Angiotensin II blockade may inhibit the transition from microalbuminuria to overt nephropathy through prevention of intrarenal angiotensin II augmentation, independently of changes in blood pressure and glucose levels.