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.

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.

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.

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.

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.

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.

Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker.

Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) is generally well-established as a treatment for nephropathy, this treatment is not fully effective in some patients. Based on the recent evidence implicating aldosterone in renal disease progression, this study was conducted to examine the efficacy of blockade with three different mechanisms by adding an aldosterone blocker in patients who do not respond adequately to the dual blockade. A 1-year randomized, open-label, multicenter, prospective controlled study was conducted, in which 32 non-diabetic nephropathy patients with proteinuria exceeding 0.5 g/day were enrolled after more than 12 weeks of ACE-I (5 mg enalapril) and ARB (50 mg losartan) combination treatment. These patients were allocated into two groups of 16 patients each: a triple blockade group in which 25 mg of spironolactone daily was added to the ACE-I and ARB combination treatment, and a control group in which 1 mg of trichlormethiazide or 20 mg of furosemide was added to the combination treatment instead of spironolactone depending upon the creatinine level. After 1 year of treatment, the urinary protein level decreased by 58% (p<0.05) with the triple blockade but was unchanged in the controls. Furthermore, urinary type IV collagen level decreased by 40% (p<0.05) with the triple blockade but was unchanged in the controls. The decreases in urinary protein and urinary type IV collagen were not accompanied by a decrease in blood pressure. Mean serum creatinine, potassium and blood pressure did not change significantly by either treatment. In conclusion, triple blockade of the RAAS was effective for the treatment of proteinuria in patients with non-diabetic nephropathy whose increased urinary protein had not responded sufficiently to a dual blockade.

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.

Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function.

AIMS: We studied whether adding the spherical adsorptive carbon AST-120 to conventional treatments is effective in inhibiting progression of chronic kidney disease (CKD) at the stage of moderate decrease in renal function. METHODS: 43 CKD patients with moderately impaired renal function indicated by glomerular filtration rate (GFR) of 20-70 ml/min as measured by non-radiolabeled iothalamate clearance method were enrolled in the study. 26 patients showing a decrease of GFR by 5 ml/min during a 1-year observation period were randomized to receive ongoing treatments only (control group, 12 cases) or with AST-120 co-administered with ongoing treatment (AST-120 group, 14 cases). The intervention period was 1 year and the change in GFR was the primary evaluation variable. RESULTS: The mean changes of GFR per month (DeltaGFR) in the intervention period were not significantly different between both groups. However, when comparing the DeltaGFR in the observation and intervention periods for each group, the rate of decline in GFR was significantly retarded (p < 0.001) in the AST-120 group while no significant difference was observed in the control group. CONCLUSION: These results suggest that co-administration of AST-120 with conventional treatments retards decline in renal function in CKD patients with moderate decrease in renal function.

Serum NTX is a practical marker for assessing antiresorptive therapy for glucocorticoid treated patients with chronic kidney disease.

INTRODUCTION: In chronic kidney disease (CKD) patients, serum concentration of type I collagen N-telopeptide (S-NTX) increases as renal function declines because of perturbed bone metabolism by renal dysfunction itself and impaired urinary excretion of NTX. Glucocorticoid (GC), which is often used for the treatment of kidney disease, may enhance bone resorption. We studied the bone resorption state in GC-treated CKD patients and the effects of bisphosphonate on S-NTX. METHODS: We measured S-NTX and creatinine clearance (Ccr) in 48 non-diabetic patients with declining renal function who had never received GC, vitamin D, calcium or bisphosphonate (reference group). Bone markers including S-NTX and BSAP (bone specific alkaline-phosphatase) in 144 patients receiving GC (prednisone equivalent of > or =2.5 mg/day) for more than 6 months (GC-treated group) were measured. We compared the GC-treated group to the reference group in a cross-sectional study. In a longitudinal study, we further followed 55 patients from the GC-treated group, whose Ccr was more than 60 mL/min (CKD stage 1 or 2) for 1 year after 2.5 mg/day of risedronate was commenced. RESULTS: In the reference group, S-NTX was correlated with Ccr (S-NTX = 456.6/Ccr + 4.5, r = 0.797, P < 0.0001). S-NTX values in the GC-treated group were higher than those found in the reference group at any Ccr. We defined the resorption index (RI) as a ratio of measured S-NTX to estimated NTX given by the correlation curve. Whereas BSAP did not change significantly, S-NTX decreased significantly by risedronate treatment. RI decreased from 1.59 (baseline) to 1.54, 1.25 (P < 0.01, versus baseline) and 1.23 (P < 0.01) at 1, 3 and 6 months after the start of therapy, respectively, which means that S-NTX values approached the correlation curve. Percent changes of S-NTX at 3 months were larger in patients with higher pretreatment S-NTX. CONCLUSION: Higher S-NTX in the GC-treated group suggests that bone resorption is enhanced by GC. In CKD patients with mild renal dysfunction, S-NTX is a practical and useful marker for monitoring bone resorption during GC treatment.

Mast cell chymase in the ischemic kidney of severe unilateral renovascular hypertension.

Chymase degrades angiotensin I (AI) to form angiotensin II (AII), probably constituting a bypass of the renin-angiotensin cascade. Chymase activity increases in some vascular diseases. In the kidney, an increase in chymase activity was reported in an animal model of ischemic kidney of renovascular hypertension (RVH); however, no such evidence has been provided in humans. We treated a 64-year-old patient with severe unilateral RVH and atherosclerosis, for whom removal of the ischemic kidney was the only option. Using immunohistochemical staining, we investigated chymase activity in the removed kidney and associated artery and vein. An increase in chymase activity, together with mast cells infiltrating the interstitium, was observed where interstitial fibrosis was seen. In the renal artery, where severe atherosclerosis was seen, and also in the vein, mast cell infiltration in the adventitia was accompanied by chymase. The captopril test showed an increase in serum aldosterone level, with a concomitant increase in plasma renin activity and decrease in blood pressure. Because the decrease in blood pressure implies a decrease in circulatory AII levels, it is plausible that in this patient, chymase had a role in AII formation in the adrenal gland to stimulate aldosterone secretion. Thus, by means of captopril, AI levels increased, and chymase may have produced AII in loci tissues, which, in turn, stimulated aldosterone secretion. This is the first report of an increase in chymase activity in the interstitium of an ischemic kidney and renal artery and vein in a patient with RVH and atherosclerosis.

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.

Effects of the oral adsorbent AST-120 on tryptophan metabolism in uremic patients.

BACKGROUND: Tryptophan (TRP), an essential amino acid, is bound mostly to albumin in plasma. However, it is reported that binding is inhibited by indoles that accumulate in uremic plasma. This may be responsible for the malnutrition observed in uremic patients. AST-120, an oral adsorbent of uremic toxins, can reduce concentrations of indoxyl sulfate (IS), the most abundant indolic metabolite in uremic plasma. We therefore investigated whether AST-120 recovers TRP binding to plasma proteins and improves the nutritional state of uremic patients. METHODS: The in vitro binding ratio of TRP to bovine serum albumin (BSA) was measured in the presence of IS by the equilibrium dialysis technique. In addition, five predialysis patients with chronic renal failure (CRF) were administered AST-120 for 2 months. Plasma concentrations of total TRP, IS, and free TRP were measured in five healthy volunteers (normal [N] group) and five patients with CRF before and after 2 weeks of AST-120 therapy (6 g/d). Their nutritional statuses also were compared before and after 2 months of AST-120 administration. RESULTS: IS inhibited in vitro binding of TRP to BSA in a dose-dependent manner. Total TRP concentrations and protein-binding ratios in patients with CRF (0.90 +/- 0.08 mg/dL and 68.7% +/- 6.8%, respectively) were significantly lower than those in the N group (2.45 +/- 0.45 mg/dL and 92.0% +/- 1.4%, respectively). However, a 2-week administration of AST-120 significantly reduced IS levels from 1.79 +/- 1.01 to 1.15 +/- 0.85 mg/dL (N group, 0.06 +/- 0.01 mg/dL), increased total TRP levels (1.16 +/- 0.18 mg/dL), and improved the TRP plasma protein-binding ratio to 83.1% +/- 3.8%, whereas total protein and albumin levels remained unchanged. After 2 months of AST-120 administration, serum albumin and transferrin levels increased significantly. CONCLUSION: AST-120 improves nutritional state, at least partly through correcting impaired TRP metabolism, in patients with CRF.

Effects of benidipine on glomerular hemodynamics and proteinuria in patients with nondiabetic nephropathy.

Experimental studies suggest that some long-acting calcium antagonists decrease glomerular hypertension and suppress the progression of nephropathy, but clinical evidence is lacking. To investigate clinically whether a long-acting calcium antagonist, benidipine, lowers glomerular capillary hydraulic pressure via a decrease in efferent arteriolar resistance and decreases proteinuria, we examined hypertensive patients with nondiabetic nephropathy. The subjects were 7 patients with chronic glomerulonephritis or glomerulosclerosis. Before and during the administration of benidipine (4 mg/day), systemic pressure, glomerular hemodynamics, the sodium sensitivity index (reciprocal of the pressure-natriuresis curve), and urinary excretion of proteins (total protein, albumin, and immunoglobulin G) were investigated. The glomerular hemodynamics in terms of glomerular capillary hydraulic pressure and resistance of afferent and efferent arterioles were calculated from the renal clearance, plasma total protein concentration, and pressure-natriuresis relationship. Benidipine lowered the mean arterial pressure from 105 +/-5 to 99 +/- 4 mm Hg (p = 0.002; mean +/- SD) and glomerular pressure from 48 +/- 8 to 39 +/- 5 mmHg (p = 0.006) by decreasing the resistance of efferent arterioles. Benidipine made the pressure-natriuresis curve steeper and decreased the median sodium sensitivity index from 0.099 (0.084 and 0.117; 25th and 75th percentiles) to 0.048 (0.017 and 0.058; p = 0.018). Urinary excretion of proteins did not change. Our clinical study showed that benidipine lowered the glomerular pressure by decreasing the resistance of efferent arterioles and decreased the sodium sensitivity of blood pressure, but did not affect proteinuria in patients with nondiabetic nephropathy.

Blunted response of the renin-angiotensin system and nitric oxide synthesis related to sodium sensitivity in immunoglobulin A nephropathy.

Sodium sensitivity of blood pressure appears before hypertension in immunoglobulin A nephropathy, as glomerulosclerosis and interstitial damage progress. To find whether this sensitivity is related to NO and the renin-angiotensin system, we examined 39 such patients without hypertension after they followed a diet with an ordinary sodium level for 1 week and a sodium-restricted diet for 1 week, in random order. Patients were divided into two groups at the median of their sodium sensitivity index (<0.040, n=19; > or =0.040 mmHg/mEq per day, n=20), calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linkage of two datum points obtained during the different diets. Urinary excretion of NOx (NO2 and NO3), plasma renin activity, and serum aldosterone were measured. NOx was higher in the low-index group than in the high-index group with the ordinary sodium level, but not during sodium restriction. NOx was correlated negatively and significantly with the index with the ordinary sodium level (p=-0.406), but correlation in changes during sodium loading was not significant (p=-0.195). Changes in plasma renin activity and serum aldosterone during sodium restriction were greater in the low-index group than in the high-index group. The changes in renin activity and aldosterone were correlated negatively and significantly with the index (p=-0.573 and -0.499, respectively). These results indicate that impairment of NO synthesis and a blunted response of the renin-angiotensin system are attributable to the altered sodium sensitivity of blood pressure in patients with immunoglobulin A nephropathy.

Role for thromboxane A2 from glomerular thrombi in nephropathy with type 2 diabetic rats.

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

[K/DOQI clinical practice guidelines for management of renal osteodystrophy in predialysis patients].

Blood levels of PTH (parathyroid hormone) begin to rise when GFR falls below 60 mL/min/1.73 m2, and evidence of bone disease due to hyperparathyroidism may be present at Stage 3 of chronic kidney disease (CKD). IntactPTH(i-PTH) is a useful test in detecting high turnover bone disorder and low turnover bone disorder. The Work Group taken target range of serum i-PTH in predialysis patients by their opinion. Dietary phosphorus should be restricted when the serum levels of i-PTH are elevated above target range of CKD stage. If phosphorus and i-PTH levels can not be controlled within the target range, despite dietary phosphorus restriction, phosphate binders should be prescribed. Only calcium based phosphate binders are available in predialysis patients in Japan. To avoid soft tissue calcification, total elemental calcium intake should not exceed 2,000 mg/day. If vitamin D deficiency are present, vitamin D2 should be supplied. But we can't measure serum 25(OH) D and prescribe vitamin D2 in Japan. Low dose of active vitamin D sterols are effective on renal osteodystrophy in predialysis patient. Active vitamin D sterols should be prescribed from low doses and serum calcium levels and renal function should be checked frequently. It is necessary to evaluate this K/DOQI (Kidney disease outcomes quality initiative) guideline and to establish guideline in Japan.

[Hyperphosphatemia and diet therapy].

Hyperphosphatemia cause not only renal bone disease but also poor prognosis in hemodialysis patients. We should control serum phosphate levels within near normal range. Although many patients are prescribed phosphate binder, they should restrict oral phosphate intake. There are poor prognosis in malnutrition patients, they should take sufficient protein. Contents of phosphate in foods increase proportionaly with protein contents. It is important that they should take foods with low phosphate contents and low phosphate/protein ratio. They should restrict preserved food, confectionary, seasoning which contain phosphate compounds as food additive. It is useful to take special low phosphate food.

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.