Efficacy and safety of daprodustat in Japanese peritoneal dialysis patients.

Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia of chronic kidney disease. This phase 3 study evaluated the efficacy and safety of daprodustat in an uncontrolled cohort of 56 Japanese peritoneal dialysis patients with anemia over 52 weeks. Subjects received daprodustat 4 mg orally once daily for 4 weeks and the dose was subsequently adjusted every 4 weeks. Mean baseline hemoglobin was 10.9 g/dL (95% CI 10.59, 11.12). Mean hemoglobin reached the target range (11.0-13.0 g/dL) at week 12 and was maintained until week 52. Mean hemoglobin during weeks 40-52 was 12.1 g/dL (95% CI 12.0, 12.2). The most frequent adverse events included nasopharyngitis (29%), catheter-site infection (18%), peritonitis (16%), diarrhea (14%), and nausea (11%). No deaths were reported. Once-daily oral daprodustat treatment was generally well tolerated and mean hemoglobin was achieved and maintained within the target range in Japanese peritoneal dialysis participants.

Development of a risk prediction model for infection-related mortality in patients undergoing peritoneal dialysis.

BACKGROUND: Assessment of infection-related mortality remains inadequate in patients undergoing peritoneal dialysis. This study was performed to develop a risk model for predicting the 2-year infection-related mortality risk in patients undergoing peritoneal dialysis. METHODS: The study cohort comprised 606 patients who started and continued peritoneal dialysis for 90 at least days and was drawn from the Fukuoka Peritoneal Dialysis Database Registry Study in Japan. The patients were registered from 1 January 2006 to 31 December 2016 and followed up until 31 December 2017. To generate a prediction rule, the score for each variable was weighted by the regression coefficients calculated using a Cox proportional hazard model adjusted by risk factors for infection-related mortality, including patient characteristics, comorbidities, and laboratory data. RESULTS: During the follow-up period (median, 2.2 years), 138 patients died; 58 of them of infectious disease. The final model for infection-related mortality comprises six factors: age, sex, serum albumin, serum creatinine, total cholesterol, and weekly renal Kt/V. The incidence of infection-related mortality increased linearly with increasing total risk score (P for trend <0.001). Furthermore, the prediction model showed adequate discrimination (c-statistic = 0.79 [0.72-0.86]) and calibration (Hosmer-Lemeshow test, P = 0.47). CONCLUSION: In this study, we developed a new model using clinical measures for predicting infection-related mortality in patients undergoing peritoneal dialysis.

Social functioning and socioeconomic changes after introduction of regular dialysis treatment and impact of dialysis modality: a multi-centre survey of Japanese patients.

AIM: Patient socialization and preservation of socioeconomic status are important patient-centred outcomes for those who start dialysis, and retention of employment is a key enabler. This study examined the influence of dialysis inception and modality upon these outcomes in a contemporary Japanese cohort. METHODS: We conducted a survey of prevalent chronic dialysis patients from 5 dialysis centres in Japan. All patients who had been on peritoneal dialysis (PD) since dialysis inception were recruited, and matched with a sample of those on in-centre haemodialysis (ICHD). We assessed patients' current social functioning (Short Form 36 Health Survey), and evaluated changes to patient employment status, annual income, and general health condition from the pre-dialysis period to the current time. RESULTS: A total of 179 patients were studied (102 PD and 77 ICHD). There were no differences in social functioning by modality. Among them, 113 were employed in the pre-dialysis period with no difference by modality. Of these, 22% became unemployed after dialysis inception, with a corresponding decline in average working hours and annual income. The odds of unemployment after dialysis inception were 5.02 fold higher in those on ICHD compared to those on PD, after adjustment for covariates. There were no changes for those who were already unemployed in the pre-dialysis period. CONCLUSIONS: Employment status is significantly hampered by dialysis inception, although PD was associated with superior retention of employment and greater income compared to ICHD. This supports a positive role for PD in preservation of socioeconomic status and potentially other patient-centred outcomes.

Brain atrophy in peritoneal dialysis and CKD stages 3-5: a cross-sectional and longitudinal study.

BACKGROUND: Brain atrophy has been reported in patients with end-stage renal disease receiving hemodialysis, although its mechanism is unknown. However, little is known regarding brain atrophy in patients receiving peritoneal dialysis (PD). Therefore, we examined brain volume and its annual change over 2 years in PD patients compared with patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). STUDY DESIGN: Cross-sectional and longitudinal cohort. SETTING & PARTICIPANTS: 62 PD patients and 69 patients with NDD-CKD with no history of cerebrovascular disease who underwent brain magnetic resonance imaging (MRI) were recruited in a cross-sectional study. Among them, 34 PD patients and 61 patients with NDD-CKD, who underwent a second brain MRI after 2 years, were recruited in a longitudinal study. PREDICTOR: PD therapy versus NDD-CKD. OUTCOMES & MEASUREMENTS: T1-weighted magnetic resonance images were analyzed. Total gray matter volume (GMV), total white matter volume (WMV), and cerebrospinal fluid space volume were segmented, and each volume was quantified using statistical parametric mapping software. Normalized GMV and WMV values were calculated by division of GMV and WMV by intracranial volume to adjust for variations in head size. We compared normalized GMV and normalized WMV between PD patients and patients with NDD-CKD in the cross-sectional study and the annual change in normalized GMV in the longitudinal study. RESULTS: In the cross-sectional study, normalized GMV, which was correlated inversely with age, was lower in PD patients than in patients with NDD-CKD. However, normalized WMV, which was not correlated with age, was comparable between the groups. Annual change in normalized GMV was significantly higher in PD patients than in patients with NDD-CKD. These differences remained significant even after adjustment for potential confounding factors. LIMITATIONS: A short observation period and high dropout rate in the longitudinal study. CONCLUSIONS: Decline in normalized GMV is faster in PD patients than in patients with NDD-CKD.

Impact of combined losartan/hydrochlorothiazide on proteinuria in patients with chronic kidney disease and hypertension.

It is unknown whether the use of diuretics is optimal over other antihypertensive agents in patients with chronic kidney disease (CKD) whose blood pressure remains uncontrolled despite treatment with renin-angiotensin system (RAS) inhibitors. In this study, we assessed the additive effects of hydrochlorothiazide (HCTZ) on reducing proteinuria in CKD patients under treatment with losartan (LS). We conducted a multicenter, open-labeled, randomized trial. One hundred and two CKD patients with hypertension and overt proteinuria were recruited from nine centers and randomly assigned to receive either LS (50 mg, n=51) or a combination of LS (50 mg per day) and HCTZ (12.5 mg per day) (LS/HCTZ, n=51). The primary outcome was a decrease in the urinary protein-to-creatinine ratio (UPCR). The target blood pressure was <130/80 mm Hg, and antihypertensive agents (other than RAS inhibitors and diuretics) were added if the target was not attained. Baseline characteristics of the two groups were similar. After 12 months of treatment, decreases in the UPCR were significantly greater in the LS/HCTZ group than in the LS group. There were no significant differences in blood pressure or the estimated glomerular filtration rate between the two groups. LS/HCTZ led to a greater reduction in proteinuria than treatment with LS, even though blood pressure in the LS group was similar to that in the LS/HCTZ group following the administration of additive antihypertensive agents throughout the observation period. This finding suggests that LS/HCTZ exerts renoprotective effects through a mechanism independent of blood pressure reduction.

Icodextrin-based continuous ambulatory peritoneal dialysis therapy effectively reduces left ventricular mass index and protects cardiac function in patients with end-stage renal disease.

Increased left ventricular mass index (LVMI) is commonly observed in patients undergoing peritoneal dialysis (PD). The present study aimed to determine the effect of icodextrin (Ico) on LVMI in PD patients with maintained residual renal function (RRF). This retrospective study included 18 patients (12 men, 6 women; average age: 62 +/- 10 years) diagnosed with indications for PD therapy and divided into two groups: those treated with Ico (Ico group) and without Ico (non-Ico group). Echocardiography was performed at the beginning of continuous ambulatory PD and after 6 and 12 months. A significant reduction in LVMI (p < 0.01) and an increase in ultrafiltration (p < 0.01) were observed after 6 months of lco treatment and were maintained for 12 months. Ejection fraction was significantly lower in the non-Ico group after 12 months (p < 0.01), but was not altered in the Ico group. Blood pressure, cardiothoracic ratio, urine volume, and N-terminal prohormone of brain natriuretic peptide were unaffected by PD treatment up to 12 months. The year-averaged ultrafiltration and the reduction in LVMI were significantly correlated (p < 0.05). Ico effectively improved LVMI and maintained ejection fraction in end-stage renal disease patients within 1 year from PD initiation. Notably, treatment with Ico resulted in a reduction of LVMI (associated with increased ultrafiltration), with no significant reduction in RRF.

[A cross-sectional study of renal function based on estimated glomerular filtration rate and urinary protein levels related to risk factors for cardiovascular events and metabolic syndrome in local residents].

OBJECTIVES: In a cross-sectional study, we investigated renal function based on estimated glomerular filtration rate (eGFR) and urinary protein levels from Specific Health Examinations in Kitakyushu city related to risk factors for cardiovascular events and metabolic syndrome in residents. METHODS: For this study, 21,625 citizens (male/female=8,637/12,988) of Kitakyushu city were investigated. Citizens were enrolled in national health insurance and data were collected from a database classified for "Specific Health Guidance" by the Kokura Medical Association health testing and services center in 2010. RESULTS: As a whole, the stage of CKD increased with age, especially among those aged 70-74 years; 32% were at CKD stage 3. Only 11% of the CKD stage 3 group had a positive urinary protein (UP) test. Subjects in stages 3-5 CKD had a higher ratio of abdominal obesity, higher systolic and diastolic blood pressure, increased fasting blood glucose, HbA1c, and fasting triglyceride levels, and lower levels of HDL-C in comparison to subjects with CKD in stages 1-2. These factors increase the complication ratio of MetS for subjects in stages 3-5. The group with a history of stroke or heart disease had a significantly lower eGFR. CONCLUSION: There is a strong relationship between CKD and risk factors for cardiovascular events and MetS. It has been indicated that lifestyle modifications, suggested by primary care doctors, are very important for the early prevention of CKD. A new preventive CKD system in Kitakyushu city, based on a Specific Health Examination, began during the fiscal year 2011, and this system is expected to decrease the incidence of end-stage renal disease and cardiovascular events.

Improvement of blood pressure control in hypertensive patients with renal diseases.

For hypertensive patients with renal diseases (RD), strict blood pressure (BP) control has been recommended in recent hypertension guidelines, such as JNC VI, JNC 7, WHO/ISH 1999 and ESH-ESC 2003. We assessed the current status of BP control and the changes of BP control before and after the publication of these guidelines in 489 hypertensive patients with or without RD (age, 19-89 years, mean 59+/-13 years) who visited the hypertension and kidney outpatient clinic at Kyushu University Hospital. The clinical characteristics of RD and non-RD patients were assessed (RD patients: age, 20-89 years, mean 60+/-13 years, n=311; non-RD patients: age, 19-86 years, mean 58+/-13 years, n=178). In addition, we compared the BP control status in 2003 to that in 1996. In 2003, the BP in RD patients was 134+/-16/78+/-10 mmHg and that in non-RD patients was 138+/-12/83+/-9 mmHg. When strict BP control was defined as <130/80 mmHg, the frequency of strict BP control in RD patients was 28.9% in 2003. In addition, the BP levels of RD patients in 2003 were significantly lower than those in 1996 (134+/-16/78+/-10 mmHg vs. 141+/-17/85+/-10 mmHg, p<0.05 for both systolic blood pressure [SBP] and diastolic blood pressure [DBP]), and the frequency of strict BP control in RD patients was higher in 2003 than in 1996 (28.9% vs. 11.8%, p<0.01). The BP levels of non-RD patients in 2003 tended to be lower than those in 1996 (138+/-12/83+/-9 mmHg vs. 141+/-13/85+/-9 mmHg, n.s.). In 2003, angiotensin II receptor blockers (ARBs) were more frequently prescribed to RD patients than to non-RD patients. Furthermore, the use of ARBs was markedly increased in 2003 compared with 1996. In conclusion, in our outpatient clinic, BP levels in hypertensive patients with RD have improved in recent years, and were lower than those in hypertensive patients without RD, which may in part reflect the physicians' awareness of the importance of strict BP control in RD patients, as suggested by several recent hypertension guidelines.

Midodrine hydrochloride and L-threo-3,4-dihydroxy-phenylserine preserve cerebral blood flow in hemodialysis patients with orthostatic hypotension.

Orthostatic hypotension (OH) after hemodialysis (HD) is a serious complication, as it causes various neurological symptoms and even ischemic brain damage. The aim of the present study was to evaluate the effects of antihypotensive agents, midodrine hydrochloride (MID) and L-threo-3,4-dihydroxyphenylserine (L-DOPS), on OH after HD. We measured systolic blood pressure (SBP) and cerebral blood flow velocity in the middle cerebral artery (MCVm, by transcranial Doppler sonography), in patients with OH during a 5-min 60-degree head-up tilt test at both before and after 4-week treatment with MID at 4 mg/day (N = 6) or L-DOPS at 400 mg/day (N = 7). Both MID and L-DOPS did not significantly protect against falls in systolic BP (SBP) after passive head-up tilt. However, a significant improvement was achieved in MCVm-decrement in the MID group at 3 min and the L-DOPS group at 0, 1 and 3 min during head-up tilt. Although MID and L-DOPS did not prevent OH after HD in HD patients, both agents preserved cerebral blood flow during orthostasis in HD patients with OH.

Increased renal resistive index in atherosclerosis and diabetic nephropathy assessed by Doppler sonography.

OBJECTIVE: The renal resistive index (RI) and pulsatility index (PI), measured using Doppler ultrasonography, reflect intrarenal vascular resistance. We evaluated the relationship between these indices and pulse wave velocity (PWV), a measure of arterial stiffness, which reflects atherosclerosis, and determined whether renal RI and PI differ depending on the underlying renal disease. METHODS: A total of 245 inpatients with or without renal impairment who underwent ultrasonographic assessment of the renal artery were enrolled in the study. Patients with renal artery stenosis or severe renal failure (serum creatinine>or=6 mg/dl) were excluded from the study. RESULTS: In univariate analysis, the RI and PI of the main renal arteries and the interlobar arteries were significantly correlated with PWV. Multivariate analyses showed that PWV was independently associated with the RI of the main renal arteries (P<0.01, R=0.256). Patients with a creatinine level less than 3 mg/dl were divided into a control group without renal diseases and three groups with different underlying renal diseases: diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis. The RI and PI of the main renal arteries and the interlobar arteries were significantly higher in patients with diabetic nephropathy than in the other three groups, even after adjusting for multiple variables, including creatinine clearance. CONCLUSION: These results suggest that the increased RI of the renal arteries is associated with the severity of systemic atherosclerosis. Furthermore, the intrarenal vascular resistance differs depending on the underlying renal disease, and appears to increase to a greater extent in diabetic nephropathy.

Recurrent nephrotic syndrome after living-related renal transplantation resistant to plasma exchange: report of two cases.

We encountered two patients of recurrent nephrotic syndrome (NS) after renal transplantation that was resistant to plasma exchange (PEX). Case 1 was a 34-year-old man with a living-related renal transplant for type-I membranoproliferative glomerulonephritis (MPGN) related end-stage renal disease (ESRD). He developed overt proteinuria 7 months post-transplant and presented with NS 5 months later. Biopsy of the transplant kidney revealed recurrent type I MPGN, but no features of acute rejection (AR) or chronic allograft nephropathy (CAN). He was treated with cyclophosphamide (CP), oral prednisolone (40 mg/d), an anti-platelet agent, heparin sulfate, and PEX, but the nephrotic state persisted and renal function was deteriorated. He recommenced hemodialysis 3 yr and 9 months after renal transplant. Case 2 was a 47-year-old male who underwent living-related renal transplant for ESRD due to focal segmental glomerulosclerosis (FSGS). He presented with proteinuria shortly after renal transplantation. He also had frequent episodes of AR. Graft biopsy revealed recurrent FSGS. Treatment of pulse methylprednisolone and PEX was transiently effective, but NS relapsed shortly after PEX. Graft biopsy at our hospital showed features of CAN with moderate interstitial fibrosis and tubular atrophy, presence of intraglomerular foam cells but no segmental sclerosis. Treatment with 12 courses of low-density lipoprotein apheresis (LDL-A) reduced proteinuria from 9.6 to 2.0 g/d, and incomplete remission has been maintained for more than 1 yr after LDL-A with slowly progressive renal dysfunction. Despite recent therapeutic advances, including the use of immunosuppressants and PEX, treatment of recurrent disease remains difficult. The LDL-A might be useful in cases with recurrent FSGS resistant to PEX.

Dialysis-related hypotension as a cause of progressive frontal lobe atrophy in chronic hemodialysis patients: a 3-year prospective study.

BACKGROUND/AIM: Brain atrophy is known to develop more rapidly in hemodialysis (HD) patients than other individuals. The present study was designed to examine the role of HD-related hypotension in brain atrophy in patients on chronic HD. METHODS: By using magnetic resonance imaging, whole brain atrophy was assessed by the ventricular-brain ratio (VBR; ventricular area/whole brain area). Frontal brain atrophy was assessed by the frontal atrophy index (FAI; frontal brain area/intracranial frontal space). The number of lacunae was also counted. We studied 32 HD patients without symptomatic neurological abnormalities or diabetes mellitus: male/female ratio 19/13; mean age +/- SD 53 +/- 10 (range 28-77) years; mean HD duration +/- SD 11 +/- 6 (range 1-22) years. Magnetic resonance imagings were taken in 1995 and 1998. All dialysis-related hypotension episodes during the same period were identified from the medical records and counted. RESULTS: The VBR ranged from 8.8 to 18.7% in 1995 (12.8 +/- 2.2%) and was not different in 1998 (13.1 +/- 2.7%). However, the VBR increased by more than 5% in 14 patients, and their HD duration of 13 +/- 6 years was significantly longer than that of 18 patients with stable VBR (p < 0.05). The FAI in 1995 was 62.2 +/- 4.2% (range 55.8-71.3%) and decreased significantly to 59.7 +/- 4.7% (range 50.2-70.9%) in 1998 (p < 0.05). The change in FAI correlated significantly with both the total number of dialysis-related hypotension episodes (r = 0.45, p < 0.05) and the increase in number of lacunae (r = 0.42, p < 0.05). CONCLUSION: Our results suggest that dialysis-related hypotension plays a role in progressive frontal lobe atrophy in HD patients.

Up-regulated interleukin-4 production by peripheral T-helper cells in idiopathic membranous nephropathy.

BACKGROUND: Helper T (Th) cells are classified into Th1 and Th2 subsets based on cytokine production and the Th1/Th2 paradigm explains differences in inflammatory effector pathways in various human diseases. Membranous nephropathy (MN) is an immune complex disease associated with Th2 nephritogenic immune response. However, overproduction of interleukin (IL)-4, a principal Th2 cytokine, has not been demonstrated. We investigated Th1/Th2 cytokine production by peripheral Th cells and its association with the degree of proteinuria in MN. METHODS: We analysed production of Th1/Th2 cytokines, interferon (IFN)-gamma and IL-4 by peripheral Th cells, using an intracellular cytokine detection method with flow cytometry in patients with MN (n = 24). The data were compared with data from healthy subjects (n = 51), subjects with minimal change nephrotic syndrome (MCNS; n = 13) and subjects with focal segmental glomerulosclerosis (FSGS; n = 12). We compared the percentages of IFN-gamma+ and IL-4+ Th cells and the peripheral Th1/Th2 ratio (IFN-gamma/IL-4 ratio) among the four groups. We also examined the association of IFN-gamma and IL-4 production with clinical parameters of MN. RESULTS: The mean percentage of IL-4+ cells in MN (3.9+/-1.2%) was significantly higher than in the control (2.4+/-1.0%), MCNS (2.3+/-1.4%) and FSGS (2.3+/-1.2%) groups (P<0.001, respectively). The Th1/Th2 ratio was significantly lower in MN (5.3+/-2.0) than in the control (8.2+/-4.2, P<0.05), MCNS (10.0+/-5.3, P<0.01) and FSGS (10.2+/-5.3, P<0.01) groups. Moreover, the percentage of IL-4+ cells correlated significantly with the amount of proteinuria in MN (r = 0.57, P<0.01). CONCLUSIONS: IL-4 production by peripheral Th cells is up-regulated in patients with MN and correlated with the severity of proteinuria. Intracellular cytokine analysis could be a useful index in idiopathic MN.

Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27.

Uraemic patients with advanced secondary hyperparathyroidism (2HPT) have nodular hyperplastic glands with a decreased vitamin D receptor (VDR) density. Previous studies have shown that nodular hyperplasia expressed a significantly lower VDR density as compared with diffuse hyperplasia, and the VDR density negatively correlated with both the glandular weight and the marker of cell proliferation. However, the mechanism by which the decreased VDR density leads to parathyroid cell proliferation remains unclear. In the myelomonocytic cell line, active vitamin D(3) is known to activate the transcription of both p21 and p27, cyclin-dependent kinase inhibitors (CDKIs), regulating the transition from the G(1) to the S phase of the cell cycle, in a VDR-dependent manner. Moreover, the overexpression of p21 and p27 inhibits cell proliferation. In order to elucidate the mechanism of parathyroid cell proliferation, the expression of CDKIs, p21 and p27, and the VDR was analysed immunohistochemically, and compared among nodular and diffuse hyperplastic parathyroid glands, and histologically normal parathyroid glands. The VDR expression in nodular hyperplasias was significantly decreased compared with either diffuse hyperplasias or normal parathyroid glands. The expression of both p21 and p27 was also significantly lower in nodular hyperplasias than in diffuse hyperplasias or normal parathyroid glands. Sections of parathyroid glands with a high expression of nuclear VDR highly expressed both p21 and p27. In nodular hyperplasias, the expression of both p21 and p27 correlated either positively with the nuclear VDR expression or inversely with the glandular weight. Therefore, the reduced expression of p21 and p27, being VDR dependent, is a major pathogenic factor for nodular parathyroid gland growth in advanced 2HPT.

Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways.

We have recently demonstrated the direct involvement of the death receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell (RTC) death. Reactive oxygen species are thought to be a major cause of cellular damage in such injury. The aim of this study was to examine the mechanism through which antioxidants ameliorate cisplatin-induced RTC death, with special emphasis on death receptor-mediated apoptotic pathways. Cisplatin was added to cultures of normal rat kidney (NRK52E) cells or injected in rats. NRK52E cells and rats were also treated with dimethylthiourea (DMTU), a hydroxyl radical scavenger. We then examined the mRNA levels of death ligands and receptors, caspase-8 activity, cell viability, cell death, renal function, and histological alterations. RT-PCR indicated cisplatin-induced upregulation of Fas, Fas ligand, and TNF-alpha mRNAs and complete inhibition by DMTU in vitro and in vivo. Cisplatin increased caspase-8 activity of NRK52E cells, and DMTU prevented such activation. Exposure to cisplatin reduced viability of NRK52E cells, examined by WST-1 assay, and increased apoptosis and necrosis of the cells, examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and fluorescence-activated cell sorter analysis. DMTU abrogated cisplatin-induced changes in cell viability and apoptosis and/or necrosis. Cisplatin-induced renal dysfunction and histological damage were also prevented by DMTU. DMTU did not hinder cisplatin incorporation into RTCs. Our results suggest that antioxidants can ameliorate cisplatin-induced acute renal failure through inactivation of the death receptor-mediated apoptotic pathways.

Usefulness of brachial-ankle pulse wave velocity measurement: correlation with abdominal aortic calcification.

At present, brachial-ankle pulse wave velocity (baPWV) can be measured easily and noninvasively. We studied the correlation between aortic damage estimated by baPWV and that determined by measuring the length of abdominal aortic calcification (AAC) on X-ray films, which parameter has been significantly associated with cardiovascular morbidity and mortality. baPWV was measured using the form PWV/ankle brachial index (ABI) device in 97 patients free of end-stage renal failure or peripheral arterial disease. baPWV correlated significantly with age (r2=0.625, p<0.0001), was significantly higher in hypertensives than in normotensives (2,109+/-67 vs. 1,623+/-93 cm/s, p<0.0001), and correlated significantly with systolic blood pressure (r2=0.64, p<0.0001) and diastolic blood pressure (r2=0.397, p<0.0001). baPWV was significantly higher in diabetic patients than in nondiabetics (2,068+/-73 vs. 1,813+/-97 cm/s, p<0.05), but was similar in normolipidemic and hyperlipidemic patients. baPWV did not correlate with body mass index, fasting plasma glucose, total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol or triglyceride levels, but correlated significantly with AAC length (r2=0.599, p<0.0001). Multiple regression analysis indicated that age, systolic blood pressure and AAC length were independent determinants of baPWV. Our results indicate that baPWV is useful for estimating aortic damage and could be a potentially useful predictor of vascular morbidity and mortality.

Impact of interferon-gamma and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japanese patients.

BACKGROUND: Cytokines have an important role in the pathogenesis and disease progression of immunoglobulin A (IgA) nephropathy. The aim of this study is to investigate the impact of gene polymorphisms of T helper cell subtype 1 (T(H)1)/T(H)2 cytokines, interferon-gamma (IFN-gamma), and interleukin-4 (IL-4) on IgA nephropathy in Japanese patients. METHODS: We investigated IFN-gamma gene (IFNG) and IL-4 gene (IL4) polymorphisms in 96 patients with biopsy-confirmed IgA nephropathy who were followed-up for more than 3 years in our outpatient clinic and 61 healthy controls by polymerase chain reaction and direct sequencing methods. IFNG polymorphism was characterized as a microsatellite of intron 1. Four alleles were identified and designated IFNG 112, 114, 116, and 118, corresponding to 12, 13, 14, and 15 repeats, respectively. A variable number of tandem repeat (VNTR) polymorphisms of IL4 also were studied, and alleles were designated IL4 B1 and B2, corresponding to 2 and 3 repeats, respectively. RESULTS: In patients with IgA nephropathy, IFNG 114 allele and IFNG 114(+/+) genotype frequencies were significantly greater than in the healthy control group (60% versus 45%; P < 0.01 and 43% versus 23%; P < 0.05, respectively), but there was no difference between the IgA nephropathy and healthy control groups in frequencies of both IL4 VNTR allele and genotype. However, frequencies of IL4 B1 allele and B1/B1 genotype in patients with progressive IgA nephropathy (end-stage renal disease or doubling of serum creatinine level; n = 34) were significantly greater than corresponding values in the nonprogression group (n = 62; 79% versus 61%; P < 0.01 and 59% versus 34%; P < 0.05, respectively). We could not confirm an association between IgA nephropathy and polymorphisms of genes involved in the renin-angiotensin system. CONCLUSION: Our results suggest that IFN-gamma and IL-4 gene polymorphisms could influence disease susceptibility and disease progression in IgA nephropathy in Japanese patients. Am J Kidney Dis 41:371-379.

Accumulation of 8-oxoguanine in the cellular DNA and the alteration of the OGG1 expression during ischemia-reperfusion injury in the rat kidney.

During ischemia-reperfusion (I/R) injury in the rat kidney, apoptosis was observed in the distal tubules of the cortico-medullary region and outer medulla (OM) while severe necrosis was seen in the proximal straight tubules of the OM. The majority of these changes disappeared within 2 weeks. We examined the contents of 8-oxo-2'-deoxyguanosine (8-oxo-dG), which is a major type of oxidative damage in DNA, in the rat kidney during I/R injury, and also investigated the expression level of the OGG1 gene encoding the 8-oxoguanine DNA glycosylase. High-performance liquid chromatography with an MS/MS analysis of the nuclear DNA revealed an immediate accumulation of 8-oxo-dG in the nuclear DNA prepared from the cortex and OM of the kidney 1h after I/R, and an immunohistochemical analysis demonstrated the immediate accumulation of 8-oxo-dG in the nuclei of renal tubular cells both in the cortex and OM. A delayed increase of cytoplasmic staining with anti-8-oxo-dG was observed only in the cortico-medulla and OM, where the cytoplasmic staining in the proximal tubular cells is higher than in the distal tubular cells. The level of cytoplasmic staining representing 8-oxo-dG in mitochondrial DNA, peaked at 6h after I/R and preceded the necrosis of proximal tubular cells in the OM. An RNase protection assay showed a high level of OGG1 mRNA in the normal kidney, and the level decreased within 3h only in the OM, and increased thereafter 1-7 days of I/R both in the cortex and OM. In situ hybridization showed higher levels of OGG1 mRNA expression in the renal tubules in the OM than in the cortex of the normal kidney, which decreased rapidly within 3h of I/R. Thus, the accumulation of 8-oxo-dG in the mitochondrial DNA rather than in nuclear DNA is likely to be involved in the pathogenic responses such as necrosis of renal tubular cells during I/R injury of the kidney, together with an altered level of OGG1 expression.

Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death.

BACKGROUND: Tumor necrosis factor (TNF) receptor family members, such as Fas and TNF receptor 1 (TNFR1), are thought to induce apoptosis in a variety of cells and organs. Although a number of potential scenarios have been postulated for the involvement of these receptors in the pathogenesis of acute renal failure (ARF), direct evidence for their involvement in death of renal tubular cells (RTCs) and renal dysfunction is preliminary. METHODS: This study examined the roles of these receptors in RTC death in two systems: (1). in vivo murine and rat models of cisplatin-induced ARF, and (2). murine proximal tubular cells (PTCs), which were isolated from C57BL/6 (B6) mice, Fas-mutant B6-lpr/lpr mice and TNFR1-deficient mice, and normal rat kidney (NRK52E) cells in vitro. RESULTS: Reverse transcription-polymerase chain reaction indicated cisplatin-induced up-regulation of Fas, Fas ligand and TNF-alpha mRNAs in the kidney in vivo and in RTCs in vitro, both in mice and rats. In contrast, the level of TNFR1 mRNA was substantial but did not change in response to cisplatin. TNF-alpha production in cell culture medium determined by enzyme-linked immunosorbent assay (ELISA) and Fas expression determined by fluorescence-activated cell sorter (FACS) analysis increased following incubation with cisplatin in B6 PTCs. In order to examine whether Fas and TNFR1 are directly involved in RTC death and renal dysfunction, we compared cell resistance to cisplatin using a cell viability assay and FACS analysis with fluorescein isothiocyanate-conjugated annexin V and propidium iodide staining. The ratios of cell viability loss and cell death, both from apoptosis and necrosis, were higher in B6 PTCs than in other cells, while the ratios were comparable between Fas-mutant PTCs and TNFR1-deficient PTCs. Caspase-8 activity was increased in B6 PTCs, but not in Fas-mutant PTCs and TNFR1-deficient PTCs. Furthermore, the renal dysfunction and RTC death, both apoptosis and necrosis, induced by cisplatin were more severe in B6 mice in vivo. CONCLUSION: Based on these data, we conclude that the Fas- and TNFR1-mediated apoptotic pathways are directly involved in the pathogenesis of cisplatin-induced RTC death process.

Infusion of radiocontrast agents induces exaggerated release of urinary endothelin in patients with impaired renal function.

BACKGROUND: The aim of the study was to examine the role of endothelin in radiocontrast-induced nephropathy (RCN) in patients with chronic renal failure. METHODS: We measured plasma endothelin-1 (ET) and the urinary excretion of endothelin-like immunoreactivity before and after infusion of radio contrast medium (CM) in patients with normal renal function (group N; n = 6; mean serum creatinine concentration, 0.8 +/- 0.1 (SEM) mg/dl), and in another group, with renal dysfunction (group R; n = 6; 2.7 +/- 0.5 mg/dl). Half-normal saline (0.45% NaCl solution) was continuously infused in all patients for 25 h, at a rate of 100 ml/h; starting from 5 h before the infusion of CM. RESULTS: Plasma ET in group R (5.2 +/- 1.4 pg/ml) was significantly higher than in group N (0.9 +/- 0.3; P << 0.01). Urinary endothelin excretion corrected by creatinine concentration (uET/Cr) in group R (7.9 +/- 2.4 mg/g Cr) was significantly higher than in group N (1.5 +/- 0.4 mg/g Cr; P << 0.05). Urinary excretion levels of N-acetyl-Beta- d-glucosaminidase (NAG) and Beta2-microglobulin (Beta2M) were also significantly higher in group R (0.8 +/- 0.2 mU/g Cr and 670 +/- 400 mg/g Cr, respectively) than in group N (0.3 +/- 0.1 and 7.5 +/- 2.2, respectively). After CM infusion, uET/Cr in group R significantly increased, to 10.7 +/- 2.6 mg/g Cr on the next day and returned to baseline level on the third day. NAG and Beta2M showed a similar pattern, but a significant change in NAG was observed on the second day in group R. In group N, uET/Cr, NAG, and Beta2M did not change after CM infusion. Plasma ET remained unchanged throughout the observation period of 4 days in both groups. No patient developed pulmonary edema or a significant rise in serum creatinine (more than 0.5 mg/dl), caused by infusion of the amount of half-normal saline used. CONCLUSIONS: In the present study, uET/Cr increased after the administration of CM only in the patients with renal impairment. This difference in endothelin reaction may be a causal one, in that patients with renal insufficiency readily develop RCN. The infusion of half-normal saline starting before CM infusion causes no side effects and is safe for the prevention of CM-induced acute renal failure. The aim of the study was to examine the role of endothelin in radiocontrast-induced nephropathy (RCN) in patients with chronic renal failure.