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1.  Progressive Renal Decline as the Major Feature of Diabetic Nephropathy in T1D 
Despite almost universal implementation of reno-protective therapies over the last 25 years, risk of ESRD in type 1 diabetes (T1D) is not decreasing, and ESRD remains the major cause of excess morbidity and premature mortality [1]. Such a state of affairs prompts a call to action. In this review we re-evaluated the proteinuria-centric model of diabetic nephropathy and showed its deficiencies. On the basis of the extensive studies that we have been conducting in the population of the Joslin Clinic, we propose that progressive renal decline, not abnormalities in urinary albumin excretion, should be considered as the major feature of disease processes leading to ESRD in T1D.
Etiology of diabetic nephropathy should be reconsidered in light of our new findings so our perspective can be broadened regarding new therapeutic targets available for interrupting the progressive renal decline in T1D. Reduction in the rate of GFR loss, not reduction of AER, should become the measure for evaluating the effectiveness of new therapeutic interventions. We need new accurate methods for early diagnosis of patients at risk of progressive renal decline or, better yet, for detecting in advance which patients will have rapid, moderate or minimal rate of progression to ESRD.
PMCID: PMC4018428  PMID: 24218296
type 1 diabetes; kidney complications; Proteinuria; progressive renal decline
2.  CKD-induced dysfunction of HDL 
Traditional risk factors do not account for increased cardiovascular disease in patients with chronic kidney disease (CKD), particularly individuals whose CKD has progressed to end-stage kidney disease requiring dialysis. CKD patients on dialysis show little to no cardiovascular benefits from lipid-lowering therapy and thus have an exaggerated residual cardiovascular risk. High density lipoprotein (HDL) quantity and functionality may explain some of the residual risk. CKD affects the composition and disrupts the functionality of HDL, including cholesterol acceptor function and inflammatory effects. Notably, although these HDL abnormalities prevail in CKD, they do not track together and thereby support the idea of separate and distinct mechanistic pathways for each critical function of HDL. Targeting individual perturbations in HDL function represents a novel approach to therapy in this population.
PMCID: PMC3951707  PMID: 24018401
HDL; Chronic Kidney Disease
3.  The biology of APOL1 with insights into the association of APOL1 variants with chronic kidney disease 
Recent studies have identified genetic variants in APOL1 that may contribute to the increased incidence of kidney disease in populations with African ancestry. Herein, we review the biology of APOL1 present in the circulation and localized to the kidney as it may contribute to the pathogenesis of APOL1 associated kidney disease.
PMCID: PMC4022720  PMID: 24233469
Genetics; apolipoprotein; HDL; APOL1; kidney; focal segmental glomerulosclerosis; HIV; HIV associated neprhopathy; hypertensive nephrosclerosis; chronic kidney disease
4.  Vasopressin and the Regulation of Aquaporin-2 
Clinical and experimental nephrology  2013;17(6):10.1007/s10157-013-0789-5.
Water excretion is regulated in large part through the regulation of the osmotic water permeability of the renal collecting duct epithelium. The water permeability is controlled by vasopressin through regulation of the water channel, aquaporin-2 (AQP2). Two processes contribute: 1) regulation of AQP2 trafficking to the apical plasma membrane; and 2) regulation of the total amount of the AQP2 protein in the cells. Regulation of AQP2 abundance is defective in several water balance disorders including many polyuric disorders and the syndrome of inappropriate antidiuresis (SIADH). Here we review vasopressin signaling in the renal collecting duct that is relevant to the two modes of water permeability regulation.
PMCID: PMC3775849  PMID: 23584881
Vasopressin; trafficking; transcription; polyuria; hyponatremia; SIADH
5.  Prevalence of anti-phospholipase A2 receptor antibodies in Japanese patients with membranous nephropathy 
Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Anti-M-type phospholipase A2 receptor (anti-PLA2R) antibodies are found in most patients with idiopathic MN (iMN) worldwide, but the prevalence of anti-PLA2R antibodies among Japanese patients with MN is unknown. In this study, we determined the prevalence of anti-PLA2R antibodies in Japanese patients with MN.
The study population of our retrospective cross-sectional consisted of 131 patients with biopsy-proven MN who had not received any immunosuppressive treatments at time of both renal biopsy and serum sample collection. Of these, 100 had iMN and 31 had secondary MN (sMN). The circulating anti-PLA2R antibodies were analyzed using a highly sensitive Western blot analysis. Analysis was performed under non-reducing conditions with a human glomerular extract at serum dilutions of 1:25, 1:10, and 1 as the primary antibody.
Anti-PLA2R antibodies were detected in 53 (53 %) of 100 patients with iMN and 0 (0 %) of 31 patients with sMN. The prevalence of anti-PLA2R antibodies was higher in patients with nephrotic syndrome (61 %) than in patients without nephrotic syndrome (43 %). The number of patients with serum albumin ≤3.0 g/dL was significantly higher in those with anti-PLA2R antibodies (92 %) than that in those without them (68 %).
Anti-PLA2R antibodies were found in Japanese patients with iMN; however, the prevalence was lower than that of any other Asian country. This may indicate that the presence of other pathogenic antigens plays a significant role in Japanese patients with iMN.
PMCID: PMC4543411  PMID: 25412738
Phospholipase A2 receptor; Antibody; Membranous nephropathy; Prevalence; Japan; Western blot
6.  Intact parathyroid hormone and whole parathyroid hormone assay results disagree in hemodialysis patients under cinacalcet hydrochloride therapy 
The parathyroid gland secretes 1-84 and 7-84 parathyroid hormone (PTH) fragments, and its regulation is dependent on stimulation of the extracellular calcium-sensing receptor. While the intact PTH system detects both PTH fragments, the whole PTH system detects the 1-84PTH but not the 7-84PTH. Cinacalcet hydrochloride (CH) binds to calcium-sensing receptor as a calcimimetic. Here we investigated the role of CH treatment in the assessment of parathyroid gland function.
Stable adult dialysis patients for whom CH therapy was planned were included. Patients for whom CH therapy was not planned were simultaneously included as the control group.
The CH group (n = 44) showed significantly higher circulating levels of Ca, intact PTH, and whole PTH, before the CH treatment than the control group (n = 112). The Ca, intact PTH, and whole PTH levels decreased along with the CH therapy, and the Ca levels became comparable in the 8th week of treatment and thereafter. The CH group in the 8th week and thereafter showed significantly lower whole/intact PTH ratios than the control group, while the whole/intact PTH ratio was not significantly different between before and during the CH therapy. A multiple regression analysis revealed that the whole/intact PTH ratio was almost constant, but both the serum Ca level and a CH therapy could potentially modify the fixed number. When the whole PTH levels were estimated by intact PTH levels using the relationship between them in the control group, the levels were clearly overestimated in the CH group.
Although the direct effect of CH on the whole/intact PTH ratio is masked by its hypocalcemic action, we could successfully demonstrate that the ratio in CH users is lower than that in the non-users with comparable levels of serum Ca. Evaluating parathyroid function with intact PTH according to the clinical practice guidelines in patients being treated with CH may lead to significant overestimation and subsequent overtreatment.
PMCID: PMC4543410  PMID: 25384431
Intact PTH; Whole PTH; Cinacalcet hydrochloride; Hemodialysis
7.  Overview of the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides 
The nomenclature and classification of vasculitis has been difficult and controversial for many decades. This is problematic for both research on vasculitis as well as clinical care of patients with vasculitis. The first (1994) International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC) proposed names and definitions for the most common forms of vasculitis. Since then, there have been substantial advances in our understanding of vasculitis and changes in medical terminology. In addition, CHCC 1994 did not propose a nomenclature for some relatively common forms of vasculitis, such as vasculitis secondary to other diseases. To address these issues, a second International Chapel Hill Consensus Conference was held in 2012. The goals were to change names and definitions as appropriate, and add important categories of vasculitis not included in CHCC 1994. This overview summarizes the 2012 CHCC and points out the changes compared to the 1994 CHCC. Notable changes include the introduction of new terms such as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and IgA vasculitis, and the inclusion of categories for variable vessel vasculitis and secondary forms of vasculitis.
PMCID: PMC4029362  PMID: 24072416
Vasculitis; classification; Chapel Hill Consensus Conference
8.  Red cell distribution width is an independent factor for left ventricular diastolic dysfunction in patients with chronic kidney disease 
The increased value of the red cell distribution width (RDW) was reported to indicate poor prognosis in patients with chronic heart failure. We evaluated the value of the RDW in the diagnosis of left ventricular diastolic dysfunction (LVDD) in patients without diastolic heart failure among the chronic kidney disease (CKD) population.
The study group consisted of 73 ambulatory patients with CKD, stages 2–5. Standard echocardiography and tissue Doppler imaging (TDI) were performed, and the level of RDW was determined. Patients were divided into four groups according to the results of peak early diastolic velocity of mitral annulus (EmLV) and the stage of CKD: group with early stage CKD (eGFR > 30 ml/min/1.73 m2) without LVDD (EmLV ≥ 8 cm/s), early stage CKD with LVDD (EmLV < 8 cm/s), group with advanced stage CKD (eGFR ≤ 30 ml/min/1.73 m2) without LVDD, and group with advanced stage CKD with LVDD.
Patients with advanced stage CKD with LVDD were characterized by higher RDW levels than patients with advanced stage CKD without LVDD and with early stage CKD groups with and without LVDD [14.5 (13.8–19.5) % vs. 13.7 (11.4–15,4) %, p = 0.049, vs. 13.8(13.1–14.9) %, p = 0.031, vs. 13.7(12.1–16.2) %, p = 0.0007], respectively. The area under the receiver operating characteristic (ROC) curve of RDW level for the detection of LVDD was 0.649, 95 % confidence interval (CI) 0.528–0.758, p = 0.021, whereas ROC derived RDW value of >13.5 % was characterized by a sensitivity of 83.3 % and specificity of 45.2 % for predicting LVDD. The only independent factor of LVDD was RDW level >13.5 % with odds ratio (OR) = 3.92 (95 % CI 1.05–14.56), p = 0.037.
RDW can be used as an additional factor for the diagnosis of LVDD in patients with advanced stage of CKD.
PMCID: PMC4543415  PMID: 25248504
RDW; Chronic kidney disease; Left ventricular diastolic dysfunction
9.  Blood pressure control and satisfaction of hypertensive patients following a switch to combined drugs of an angiotensin receptor blocker and a calcium channel blocker in clinical practice of nephrology 
Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood.
This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients’ questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients’ satisfaction with regard to combination drugs.
Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients.
Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints.
PMCID: PMC4469305  PMID: 25135635
Angiotensin receptor blockers; Calcium channel blockers; Combination antihypertensive drugs; Hypertension; Blood pressure
10.  A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney 
The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO.
To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks.
CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining.
Furthermore, PCR analysis demonstrated that TGF-β and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis.
We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.
PMCID: PMC4108904  PMID: 22678524
Carbamylated erythropoietin; Remnant kidney; Apoptosis; TGF-β
11.  Cardiovascular remodeling during long-term nocturnal home hemodialysis 
Cardiovascular disease is the leading cause of morbidity and mortality in patients with kidney failure. Nocturnal home hemodialysis (NHD) is a form of kidney replacement therapy whereby hemodialysis is performed for at least 6-h overnight, at least 4 days per week. Little is known about the effects of NHD on cardiovascular remodeling as assessed by transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR).
The primary objective of the study was to determine the long-term effects of NHD on cardiovascular remodeling using different imaging modalities over a one-year follow-up.
Methods and results
A total of 11 patients were included in the study (6 males, mean age 48 ± 16 years) between 2009 and 2011 inclusive at a single tertiary care center. All patients underwent TTE and CMR at baseline and after 1 year of NHD. Left ventricular mass index decreased significantly at 1 year by both TTE (152 ± 7–129 ± 8 g/m2, p < 0.05) and CMR (162 ± 4–124 ± 4 g/m2, p < 0.05). There was also a significant decrease in both left and right atrial volume as well as in right ventricular mass index over 1 year of follow-up. Diastolic dysfunction, graded from 0 to 4, improved from a baseline grade of 3.4 to 1.2 at 1-year follow-up.
Long-term nocturnal hemodialysis leads to favorable cardiovascular remodeling with a reduction in cavity dimensions, regression of left ventricular hypertrophy, and an improvement in diastolic function, as assessed by both TTE and CMR.
PMCID: PMC4469297  PMID: 24894700
Home hemodialysis; High dose hemodialysis; Left ventricular hypertrophy; Cardiac imaging
12.  Efficacy of cyclosporine combination therapy for new-onset minimal change nephrotic syndrome in adults 
Cyclosporine and prednisolone combination therapy has been used in the treatment of minimal change nephrotic syndrome (MCNS). However, few studies have evaluated the efficacy of cyclosporine combined with intravenous methylprednisolone pulse therapy (MPT) as a first-line treatment for new-onset MCNS. We conducted a retrospective clinical study to evaluate the efficacy and safety of cyclosporine combined with MPT and oral prednisolone for new-onset MCNS in adults.
Forty-six adult patients with biopsy-proven MCNS were analyzed retrospectively. This study included three groups. Group 1 (n = 17) was treated with intravenous MPT (0.5 or 1.0 g/day for 3 days) followed by oral cyclosporine (2–3 mg/kg/day) and prednisolone (30 mg/day). Group 2 (n = 15) was treated with intravenous MPT followed by oral prednisolone (0.4–0.8 mg/kg/day). Group 3 (n = 14) was treated with oral prednisolone (0.6–1.0 mg/kg/day) alone.
The length of hospital stay was the shortest in Group 1 (P < 0.001). The mean duration to achieve <20 mg/day of prednisolone was also the shortest in Group 1 (P < 0.05). Complete remission rates were 100 % in Group 1, 85.7 % in Group 2, and 69.2 % in Group 3 during the 9-month follow-up (P = 0.073). The rate of adverse effects caused by prednisolone was less in Group 1 (P < 0.05). Multivariate analysis revealed that the independent determinants of durations of remission were the selectivity index (P = 0.004), eGFR (P = 0.001) and the use of cyclosporine (P = 0.045).
Combination therapy with cyclosporine may be a beneficial treatment option for new-onset MCNS in adults because of its clinical efficacy and safety.
PMCID: PMC4412585  PMID: 24771147
Cyclosporine; Minimal change nephrotic syndrome; Prednisolone; Clinical efficacy; Drug nephrotoxicity
13.  Mechanisms Stimulating Muscle Wasting in Chronic Kidney Disease: The Roles of the Ubiquitin-Proteasome System and Myostatin 
Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle yielding fragments that are substrates which are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF1 and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting suggesting that therapies which block myostatin could prevent muscle wasting in catabolic conditions.
PMCID: PMC3628947  PMID: 23292175
ubiquitin-proteasome system (UPS); muscle wasting; protein degradation; chronic kidney disease (CKD); caspase-3
14.  Hyperbaric area index calculated from ABPM elucidates the condition of CKD patients: the CKD-JAC study 
High prevalence of masked hypertension as well as persistent hypertension was observed in the Chronic Kidney Disease Japan Cohort (CKD-JAC) study. We proposed a novel indicator of blood pressure (BP) load, hyperbaric area index (HBI), calculated from ambulatory blood pressure monitoring (ABPM) data. The characteristic of this index and its relationship with kidney function were also evaluated.
The CKD-JAC study, enrolled 2,977 patients, is a prospective observational study started in September 2007. ABPM was conducted in a sub-group from September 2007 to April 2010 and baseline ABPM data of 1,075 subjects (63.4 % male, 60.7 years old) were analyzed.
Mean systolic HBI of male and female patients were 242.3 and 176.5 mmHg×h, respectively. HBI sensitively reflected sex (54.7 mmHg×h higher in males than in females), seasonal effects (51.6 mmHg×h higher in winter than in summer), and advancing CKD stage [(16.5 mmHg×h higher) per −10 mL/min/1.73 m2 in eGFR]. The HBI was a significant factor to associate with reduced kidney function, after adjusting with nocturnal BP change (NBPC), sex, and other variables (p value <0.001).
Our findings suggested that HBI might be a novel sensitive indicator for the reduction of kidney function, independent of patterns of NBPC.
PMCID: PMC4335270  PMID: 24682891
Chronic kidney disease; Hypertension; Hyperbaric area index; Ambulatory blood pressure monitoring (ABPM); Blood pressure load
15.  Beneficial effect of LDL-apheresis in refractory nephrotic syndrome 
LDL-apheresis is a method to correct dyslipidemia rapidly. It is expected to alleviate the tissue toxicity of persistent dyslipidemia in not only primary, but also in secondary dyslipidemia associated with refractory nephrotic syndrome, and to have a protective effect against glomerular and tubular injury as expected in atherosclerosis. In addition, the effectiveness of LDL-apheresis to promote the remission of nephrotic syndrome has been recognized. In Japan, LDL-A to control hyperlipidemia in patients with refractory nephrotic syndrome associated with focal segmental glomerulosclerosis is covered by national health insurance. Here, the hypothetical mechanism behind its effect and the evidence for its effectiveness over a long period are reviewed.
PMCID: PMC3994285  PMID: 24535024
LDL-apheresis; Nephrotic syndrome; Secondary hyperlipidemia; Lipid nephrotoxicity; Cohort study
16.  The role of a low glomerular density and being overweight in the etiology of proteinuria in CKD patients without known glomerular diseases 
Among the proteinuric patients with chronic kidney disease (CKD) who undergo a renal biopsy, we sometimes encounter those who cannot be classified as having a known primary or secondary glomerular disease. The pathogenesis and pathophysiology of these CKD patients have not been sufficiently elucidated.
We recruited 34 proteinuric patients without known glomerular diseases. The glomerular volumes (GV) of the biopsy specimens from those patients were determined by a morphometric analysis. Glomerular hypertrophy (GH) was defined as having more than 3.6 × 106 μm3. The patients were divided in two groups: those with GH (Group 1) and those without GH (Group 2). We compared the clinical and pathological parameters between Group 1 and Group 2, and among the three groups of patients: non-obese, overweight and obese group.
The patients with Group 1 had significantly higher values for the proportion of males, the body mass index (BMI), uric acid and significantly lower values for the glomerular density (GD). Of note, a multivariate regression analysis revealed that sex, the BMI and GD were significant factors correlated with the mean GV. The values for the mean GV were significantly higher in the overweight and obese groups as compared to the non-obese group, and the values for the GD were significantly lower in the obese group than in the non-obese group.
We identified a subgroup of patients who were characterized as having a high BMI and GV, and a low GD among the proteinuric CKD patients without known glomerular diseases.
PMCID: PMC4271132  PMID: 24509731
Chronic kidney disease; Glomerular hypertrophy; Proteinuria; Overweight; Obesity; Body mass index; Renal biopsy; Glomerular density
17.  Budget impact analysis of chronic kidney disease mass screening test in Japan 
Our recently published cost-effectiveness study on chronic kidney disease mass screening test in Japan evaluated the use of dipstick test, serum creatinine (Cr) assay or both in specific health checkup (SHC). Mandating the use of serum Cr assay additionally, or the continuation of current policy mandating dipstick test only was found cost-effective. This study aims to examine the affordability of previously suggested reforms.
Budget impact analysis was conducted assuming the economic model would be good for 15 years and applying a population projection. Costs expended by social insurers without discounting were counted as budgets.
Annual budget impacts of mass screening compared with do-nothing scenario were calculated as ¥79–¥−1,067 million for dipstick test only, ¥2,505–¥9,235 million for serum Cr assay only and ¥2,517–¥9,251 million for the use of both during a 15-year period. Annual budget impacts associated with the reforms were calculated as ¥975–¥4,129 million for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥963–¥4,113 million for mandating serum Cr assay only and abandoning dipstick test.
Estimated values associated with the reform from ¥963–¥4,129 million per year over 15 years are considerable amounts of money under limited resources. The most impressive finding of this study is the decreasing additional expenditures in dipstick test only scenario. This suggests that current policy which mandates dipstick test only would contain medical care expenditure.
PMCID: PMC4271136  PMID: 24515308
CKD; Budget impact; Dipstick test; Mass screening; Proteinuria; Serum creatinine assay
18.  Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy 
The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity.
We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years.
Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B.
Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.
PMCID: PMC4194014  PMID: 24477513
IgA nephropathy; Disease activity; Underglycosylated IgA; Immune complex; Biomarker
19.  Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout 
Topiroxostat, a selective xanthine oxidase inhibitor, shows effective reduction in the serum urate level in hyperuricemic patients with or without gout. The objective of this study was to evaluate the efficacy and safety of topiroxostat in hyperuricemic stage 3 chronic kidney disease patients with or without gout.
The study design was a 22-week, randomized, multicenter, double-blind study. The enrolled patients were randomly assigned to treatment with topiroxostat 160 mg/day (n = 62) or to the placebo (n = 61). The endpoints were the percent change in the serum urate level, change in the estimated glomerular filtration rate, the urinary albumin-to-creatinine ratio, the proportion of patients with serum urate levels of 356.88 μmol/L or less, blood pressure, and serum adiponectin.
After 22 weeks, although the changes in the estimated glomerular filtration rate and blood pressure were not significant, the percent change in the serum urate level (−45.38 vs. −0.08 %, P < 0.0001) and the percent change in urinary albumin-to-creatinine ratio (−33.0 vs. −6.0 %, P = 0.0092) were found to have decreased in the topiroxostat as compared with the placebo. Although the incidence of ‘alanine aminotransferase increased’ was higher in the topiroxostat, serious adverse event rates were similar in the two groups.
Topiroxostat 160 mg effectively reduced the serum urate level in the hyperuricemic stage 3 chronic kidney disease patients with or without gout.
PMCID: PMC4271138  PMID: 24448692
Hyperuricemia; Gout; CKD; Topiroxostat; FYX-051
20.  Umbilical hernia in autosomal dominant polycystic kidney disease 
PMCID: PMC4335090  PMID: 24408221
Umbilical hernia; Autosomal dominant polycystic kidney disease
21.  Significance of combined cyclosporine−prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial  
Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations.
IMN patients with SRNS (age 16–75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2–3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks.
Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3–1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications.
CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2–3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.
PMCID: PMC4194018  PMID: 24363128
Cyclosporine; Idiopathic membranous nephropathy; Steroid-resistant nephrotic syndrome; Once-a-day administration; Preprandial administration; Therapeutic drug monitoring
22.  Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy  
Dyslipidemia is an independent risk factor for the development and progression of diabetic nephropathy (DN). In this review, we summarize mouse models with both diabetes and dyslipidemia, and their associated complications. We then discuss molecules potentially involved in deterioration of DN by dyslipidemia. We focus especially upon toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), since we have found that their mRNA levels are commonly increased in glomeruli of type 1 (streptozotocin [STZ]-induced) and type 2 (A-ZIP/F-1 lipoatrophic) diabetic mice. Gene expression of MRP8 and Tlr4 is further upregulated during worsening of STZ-induced DN by a high fat diet (HFD). Moreover, these HFD-induced changes are accompanied by enhanced gene expression of CCAAT element binding protein β and phosphorylation of c-Jun N-terminal kinase in the kidney, which have also been reported in pancreatic β cells under diabetic-hyperlipidemic conditions. Effects of a HFD upon DN are cancelled in Tlr4 knockout mice. Macrophages are the predominant source of MRP8 in glomeruli. In cultured macrophages, combinatorial treatment with high glucose and palmitate amplifies MRP8 expression in a Tlr4-dependent manner, and recombinant MRP8 protein markedly increases gene expression of the inflammatory cytokines interleukin-1β and tumor necrosis factor α. Here, we propose ‘macrophage-mediated glucolipotoxicity’ via activation of MRP8/TLR4 signaling as a novel mechanism of pathophysiology for DN.
PMCID: PMC4139582  PMID: 24357461
Diabetic nephropathy; Glucolipotoxicity; Macrophage; Toll-like receptor
23.  Clinical studies of the Research Committee on Intractable Vasculitides, the Ministry of Health, Labour and Welfare of Japan 
In Japan, the Research Committee on Intractable Vasculitides, supported by the Ministry of Health, Labour and Welfare, has been promoting basic and clinical research on vasculitis since 1972. The present Research Committee on Intractable Vasculitides comprises 4 subcommittees under the direction of a Principal Investigator: Basic and Pathological Research Subcommittee, Clinical Research Subcommittee of Small and Medium-sized Vessel Vasculitis, Clinical Research Subcommittee of Large-sized Vessel Vasculitis, and International Cooperation Research Subcommittee. Since 2008, 9 nationwide clinical studies for vasculitis have been conducted and 8 clinical and basic studies are in progress.
PMCID: PMC3824225  PMID: 24091919
Antineutrophil cytoplasmic antibody-associated vasculitis; Eosinophilic granulomatosis with polyangiitis; Granulomatosis with polyangiitis; Microscopic polyangiitis
24.  Estimated glomerular filtration rate and daily amount of urinary protein predict the clinical remission rate of tonsillectomy plus steroid pulse therapy for IgA nephropathy 
This retrospective study was designed to estimate the clinical remission (CR) rate of tonsillectomy plus steroid pulse (TSP) therapy in patients with IgA nephropathy.
Based on 292 of 302 patients with IgA nephropathy treated at 11 Japanese hospitals, we constructed heat maps of the CR rate at 1 year after TSP with the estimated glomerular filtration rate (eGFR), grade of hematuria, pathological grade, number of years from diagnosis until TSP, and age at diagnosis on the vertical axis and the daily amount of urinary protein (urinary protein) on the horizontal axis. We compared subgroups usinge Student’s t test, the chi-square test with Yates correction, or Fisher’s exact probability test.
The first heat map of eGFR and urinary protein showed that the CR rate was 71 % (CR vs. non-CR, 96 vs. 40) in patients with eGFR greater than 30 ml/min/1.73 m2 and 0.3–1.09 g/day of urinary protein. However, the CR rate in patients with more than 1.50 g/day of urinary protein was approximately 30 %. The second heat map of grade of hematuria and urinary protein revealed that the CR rate is 72 % (CR vs. non-CR, 93 vs. 37) in patients with more than 1+ hematuria and 0.3–1.09 g/day of urinary protein; however, it was 28.6 % in patients with no hematuria. The third heat map of pathological grade and urinary protein demonstrated that the highest CR rate was 83 % (CR vs. non-CR, 52 vs. 11) in patients with pathological grade I or II disease and less than 1.09 g/day of urinary protein, as opposed to 22 % (CR vs. non-CR, 9 vs. 32) in patients with pathological grade III or IV disease and more than 2.0 g/day of urinary protein. The fourth heat map of the number of years from diagnosis until TSP and urinary protein revealed that the former did not influence the CR rate in patients with less than 1.09 g/day of urinary protein. However, in patients with more than 1.10 g/day of urinary protein, the CR rate of the subgroup with less than 6 years was 43 % (CR vs. non-CR; 23 vs. 54) compared to 23 % (CR vs. non-CR, 11 vs. 48; P = 0.01) in the subgroup with more than 6 years. The fifth heat map of age at diagnosis and urinary protein showed that the CR rate is approximately 72 % (CR vs. non-CR, 73 vs. 28) in patients older than 19 years at diagnosis with 0.3–1.09 g/day of urinary protein.
The daily amount of urinary protein is an important predictor of the CR rate after TSP in IgA nephropathy patients. Heat maps are useful tools for predicting the CR rate associated with TSP.
PMCID: PMC4139581  PMID: 24052158
Clinical remission; Heat map; IgA nephropathy; Tonsillectomy plus steroid pulse therapy
25.  Safety and efficacy of skin patches containing loxoprofen sodium in diabetic patients with overt nephropathy 
Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy.
Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations.
The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR.
Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.
PMCID: PMC4059959  PMID: 23921417
Skin patches; Loxoprofen; Diabetic nephropathy; Type 2 diabetes; Prostaglandin E2; GFR; NSAIDs

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