[Show abstract][Hide abstract] ABSTRACT: Objective Immunoglobulin A nephropathy (IgAN) exhibits a peak onset that coincides with the reproductive age. Therefore, many young women with IgAN may become pregnant. However, the outcome of pregnancy in women with renal diseases remains controversial, and the characteristics and outcome of pregnancy in IgAN patients must be further evaluated. Methods A prospective follow-up study of 64 pregnant women with IgAN was performed by analyzing the laboratory data and prognosis. To clarify the influence of renal insufficiency, we compared these patients according to the chronic kidney disease (CKD) stage with special attention to CKD stage 3 [N=16 in total, N= 9 for estimated glomerular filtration rate (eGFR) ≥45 mL/min, N=7 for <45 mL/min]. Results We found that pregnancy and delivery did not produce any significant changes in the renal function for patients with CKD stage 3 (≥45 mL/min) at five years after delivery, although proteinuria was elevated at 30 weeks of pregnancy and at three months after delivery. However, only for patients with CKD stage 3 (<45 mL/min) was there a significant deterioration in the eGFR at five years after delivery. Additionally, the data of pregnant women with CKD stage 3 were compared with those of 22 nonpregnant women with similar clinical and demographic characteristics. Conclusion Pregnant patients with IgAN (CKD stage 3, eGFR ≥45 mL/min) did not exhibit any significant reduction in the renal function at five years after delivery as compared with the baseline, which was similar to the findings in nonpregnant patients. Thus, while pregnancy with CKD stage 3 (eGFR ≥45 mL/min) was not a risk factor, patients with CKD stage 3 (eGFR <45 mL/min) showed a worsened renal function five years after delivery.
[Show abstract][Hide abstract] ABSTRACT: A 48-year-old male was admitted to our hospital with nephrotic syndrome. Light-microscopic examination of a renal biopsy specimen showed almost normal glomerular appearance, however, immunofluorescence examination revealed linear and granular IgG deposits on the glomerular basement membrane (GBM), accompanied by slight IgG deposition in the tubular basement membrane (TBM). Further investigation of the IgG subclass and light chain staining revealed that the glomerular deposits were composed of IgG1 and IgG4, with both κ and λ light chains, while the tubular deposits were composed of only IgG4 and κ light chains. The electron-microscopic findings of small granular deposits in the GBM and TBM closely resembled those of light and heavy chain deposition disease (LHCDD). Immunoelectron microscopy confirmed the presence of κ and λ chains in the GBM and TBM, however, only significant κ chain deposition was found in the TBM. There was no evidence of monoclonal gammopathy. Clinically, the patient subsequently developed neutropenia and thrombocytopenia associated with the presence of anti-neutrophil antibody and anti-GPIIb/IIIa antibody-producing B cells in the blood. Oral steroid administration was initiated, which led to amelioration of the neutropenia, thrombocytopenia and proteinuria. This may be a very rare case of combined IgG4κ and IgG1λ deposition disease accompanied by autoimmune neutropenia (AIN) and immune thrombocytopenia (ITP) suggestive of biclonal immunoglobulin deposition disease (BIDD). Investigation of the IgG subclass and of the light chains was useful for recognizing the clonality of the immunoglobulin deposits in the kidney.
[Show abstract][Hide abstract] ABSTRACT: Caveolae on human renal glomerular endothelial cells (HRGECs) are increased in glomerular disease and correlate with the degree of albuminuria. To assess the mechanism by which caveolae contribute to albuminuria, we investigated whether albumin enters into HRGECs through caveolae. HRGECs were incubated with Alexa Fluor 488 labeled BSA or transferrin, followed by immunofluorescence localization with antibody to caveolin-1 (Cav-1), the main structural protein of caveolae, or clathrin, the major structural protein of clathrin coated pits, to assess whether BSA colocalized with Cav-1. HRGECs were also incubated with albumin and caveolae disrupting agents, including methyl beta cyclodextrin (MBCD) and nystatin, to determine whether disrupting caveolae interfered with albumin endocytosis into HRGECs. HRGECs were also incubated with albumin after transfection with Cav-1 small interfering RNAs (siRNAs). Labeled BSA colocalized with Cav-1, but not with clathrin. In contrast, labeled transferrin colocalized with clathrin, but not with Cav-1. Incubation of HRGECs with MBCD or nystatin, or transfection with Cav-1 siRNA, significantly reduced the intracellular amounts of albumin and Cav-1, relative to normal HRGECs, as shown by western blotting and immunofluorescence. These findings indicate that albumin enters HRGECs through the caveolae, suggesting that caveolae play an important role in the pathogenesis of albuminuria by providing a pathway through which albumin can enter glomerular endothelial cells. This article is protected by copyright. All rights reserved
No preview · Article · Jan 2015 · Journal of Cellular Biochemistry
[Show abstract][Hide abstract] ABSTRACT: This study was to evaluate the long-term efficacy and safety of a single-dose rituximab regimen rituximab treatment in adult patients with steroid-dependent minimal change nephrotic syndrome (MCNS).
We conducted a prospective cohort study with historical controls to evaluate the effect of single-dose infusions of rituximab at 375 mg/m2 BSA per dose administered at intervals of 6 months for a period of 24 months. At the end of the 24-month period, the patients were divided into the treatment continuation (n = 20) and treatment discontinuation (n = 5) groups according to their intention to continue/discontinue the treatment.
A significant reduction in the total number of relapses was observed during the 24-month period after the first rituximab infusion as compared with that during the 24-month period before the first rituximab infusion (108 vs. 8, P < 0.001). Complete remission was induced/maintained in all patients from 12 to 24 months after the first rituximab infusion. In regard to the clinical course after 24 months, 4 of the 20 patients in the treatment continuation group discontinued the rituximab treatment after the fifth infusion and 2 patients discontinued the treatment after the sixth infusion. However, complete remission was maintained in all the 20 patients of this group during the 12-month observation period after the first four single-dose rituximab infusions. On the other hand, 1 of the 5 patients in the treatment discontinuation group developed relapse during the observation period after the first four rituximab infusions, and the rituximab treatment was resumed.
In our trial, rituximab therapy was associated with maintenance of complete remission. Complete remission was maintained even in most of the patients who showed B-cell repletion after discontinuation of rituximab therapy. Thus, rituximab may be considered as a radical therapeutic agent for patients with steroid-dependent MCNS.
[Show abstract][Hide abstract] ABSTRACT: Purpose
The susceptible age for IgA nephropathy (IgAN) is 60 years, and its characteristics remain unknown.
We divided 600 IgAN patients into three groups: advanced-age group (AAG, n = 31, ≥60 years); middle-aged group (MAG, n = 162, 40–59 years); and young-aged group (YAG, n = 407, 20–39 years). We analyzed clinical and histological background, renal outcome, and risk of progression.
In the AAG, mean arterial pressure (MAP) and the number of hypertensive patients were significantly higher than in the YAG. Total protein, serum albumin, and estimated glomerular filtration rate were significantly lower, and blood urea nitrogen, proteinuria, and N-acetyl-β-d-glucosaminidase were significantly higher in the AAG than in MAG and YAG. In histological findings, interstitial fibrosis/tubular atrophy by Oxford classification and arteriosclerosis were more severe in the AAG than the in YAG. Renal survival rate analyzed by Kaplan–Meier method was significantly lower in the AAG (22.9 %/19 years in the AAG vs. 69.2 and 84.9 %/20 years in the MAG and YAG, p 70 % developed ESRD within 20 years.
No preview · Article · Nov 2014 · International Urology and Nephrology
[Show abstract][Hide abstract] ABSTRACT: Background:
Myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA) represents the serological hallmark of ANCA-associated vasculitis (AAV). We evaluated the analytical and diagnostic accuracy of chemiluminescence enzyme immunoassay (CLEIA) versus enzyme-linked immunosorbent assay (ELISA) for the detection of MPO-ANCA.
A total of 242 sera obtained from 51 patients with AAV and 103 patients without AAV were tested for MPO-ANCA by ELISA (NephroScholor MPOANC II) and CLEIA (the STACIA MEBLux test). Disease activity in the patients with AAV was determined based on the Birmingham Vasculitis Activity Score. We analyzed the correlations between the MPO-ANCA titers determined by the CLEIA and those determined by the ELISA, and also between the MPO-ANCA titers and the disease activity.
The MPO-ANCA titers determined by the CLEIA (x) were strongly correlated with those determined by the ELISA (y). The correlation could be expressed by the following equation in this study: y = 1.8x + 7.7 (r = 0.96; p < 0.0001). At the cutoff value of 3.5 U/ml, the CLEIA yielded positive test results for MPO-ANCA in 73 of the 242 sera (30.2%), while at the cutoff value of 20 U/ml, ELISA yielded positive test results in 57 of the 242 sera (23.6%). The CLEIA yielded false-positive test results in 4 of the 120 sera obtained from the non-AAV patients (3.3%), whereas the ELISA yielded a false-positive result in only 1 of the 120 sera obtained from the non-AAV patients (0.8%). The sensitivity and specificity of the CLEIA for the diagnosis of AAV were 100% and 96.7%, respectively, while those of the ELISA were 94.3% and 99.2%, respectively. The sensitivity and specificity of the CLEIA for the prediction of active disease were 100% and 64.4%, respectively, while those of the ELISA were 94.3% and 73.6%, respectively.
The false positivity rate of the CLEIA for MPO-ANCA tended to be high as compared with that of the ELISA. Also, according to the correlation coefficient between the results of the CLEIA and the ELISA calculated in this study, it is necessary to pay attention to the differences in the sensitivity and specificity between CLEIA and ELISA.
No preview · Article · Nov 2014 · Modern Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Background:
High uric acid level is a known risk factor for deterioration of renal function in chronic kidney disease (CKD), but its influence on the progression of IgA nephropathy (IgAN) remains unclear.
Adult IgAN patients (n = 611) were classified according to CKD stage. Renal survival rates and clinical and histological findings were compared between patients with high (H-UA) and normal (N-UA) uric acid levels in different CKD stages.
The proportion of patients with H-UA increased significantly with increasing CKD stage (stage G1, 12.3%; stage G2, 19.0%; stage G3a, 43.7%; stage G3b-4, 69.0%; P < 0.001). The 30-year renal survival rate was similar in patients with H-UA and N-UA in CKD stages G1, G2, and G3b-4, but was significantly lower in patients with H-UA than with N-UA in CKD stage G3a (24.7 vs. 51.9%; P = 0.0205). The clinical findings were similar in patients with H-UA and N-UA, but the interval from onset to biopsy differed between groups. The proportion of patients with global sclerosis was significantly higher in patients with H-UA than with N-UA in CKD stage G3a (33.3 vs. 11.4%; P = 0.0005), but the Oxford classifications were similar between groups. Multivariate Cox regression analysis identified H-UA (HR 1.36, 95% CI 1.07-1.72, P = 0.011) and a large amount of proteinuria (HR 1.38, 95% CI 1.09-1.74, P = 0.0084) as independent predictors of end-stage renal disease.
H-UA induced global glomerular sclerosis and accelerated the progression of IgAN in CKD stage G3a.
No preview · Article · Oct 2014 · Journal of nephrology
[Show abstract][Hide abstract] ABSTRACT: Hyperuricemia is a frequent complication of chronic kidney disease (CKD). Febuxostat is a novel xanthine oxidase inhibitor that is metabolized by many metabolic pathways in the kidney and the liver. We performed a 1-year cohort study of 73 hyperuricemic patients who had an estimated glomerular filtration rate (eGFR) below 45 ml/min and were being treated with urate-lowering therapy. In 51 patients, treatment was changed from allopurinol to febuxostat, and the other 22 patients were continued on allopurinol. The serum levels of uric acid (UA) level, creatinine, and other biochemical parameters were measured at baseline and after 3, 6, 9, and 12 months of treatment. The serum UA levels significantly decreased from 6.1 ± 1.0 to 5.7 ± 1.2 mg/dl in the febuxostat group and significantly increased from 6.2 ± 1.1 to 6.6 ± 1.1 mg/dl in the allopurinol group. The eGFR decreased 27.3 to 25.7 ml/min in the febuxostat group and from 26.1 to 19.9 ml/min in the allopurinol group. The switch from allopurinol to febuxostat was significantly associated with the changes in eGFR according to a multiple regression analysis (β = -0.22145, P < 0.05). Febuxostat reduced the serum UA levels and slowed the progression of renal disease in our CKD cohort in comparison with allopurinol.
[Show abstract][Hide abstract] ABSTRACT: Little is known about the long-term prognosis of patients with IgA nephropathy (IgAN).
This retrospective cohort analysis evaluated clinical and histological findings at the time of renal biopsy, initial treatment, patient outcomes over 30 years, and risk factors associated with progression in 1,012 patients diagnosed with IgAN at our center since 1974.
Of the 1,012 patients, 40.5% were male. Mean patient age was 33±12 years and mean blood pressure was 122±17/75±13 mmHg. Mean serum creatinine concentration was 0.89±0.42 mg/dL, and mean estimated glomerular filtration rate (eGFR) was 78.5±26.2 ml/min/1.73 m2. Mean proteinuria was 1.19±1.61 g/day, and mean urinary red blood cells were 36.6±35.3/high-powered field. Histologically, mesangial hypercellularity was present in 47.6% of patients, endothelial hypercellularity in 44.3%, segmental sclerosis in 74.6%, and tubular atrophy/interstitial fibrosis in 28.8% by Oxford classification. Initial treatment consisted of corticosteroids in 26.9% of patients, renin-angiotensin-aldosterone system inhibitor in 28.9%, and tonsillectomy plus steroids in 11.7%. The 10-, 20-, and 30-year renal survival rates were 84.3, 66.6, and 50.3%, respectively. Tonsillectomy plus steroids dramatically improved renal outcome. Cox multivariate regression analysis showed that higher proteinuria, lower eGFR, and higher uric acid at the time of renal biopsy were independent risk factors for the development of end stage renal disease (ESRD).
IgAN is not a benign disease, with about 50% of patients progressing to ESRD within 30 years despite treatment.
[Show abstract][Hide abstract] ABSTRACT: Background:
The renoprotective pleiotropic effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has recently been reported by several investigators. However, the effect of statins on IgA nephropathy (IgAN) is still unknown.
We selected 24 IgAN patients who had newly started statin therapy and were not treated with steroids and immunosuppressive agents during the observation period. We analyzed and compared clinical findings 1 year before and after treatment.
Mean age was 50.5 ± 9.91 years and mean blood pressure was 90.9 ± 10.8 mmHg. Renal function was slightly deteriorated, serum creatinine was 1.03 (0.71-1.24) mg/dL and estimated glomerular filtration rate (eGFR) was 55.8 ± 22.8 mL/min. Lipid metabolism was poorly controlled [total cholesterol 247.7 ± 35.7 mg/dL, low-density lipoprotein cholesterol 151.5 (140.8-172.8) mg/dL, and triglyceride 163.0 (126.3-243.8) mg/dL]. Mild urinary abnormality was observed [proteinuria: 0.50 (0.22-1.29) g/g creatinine, urinary red blood cells 1.0 (0.2-5.0) per high power field]. After 1 year of statin treatment, lipid control was significantly better than at baseline. Proteinuria was not significantly decreased but renal function was improved. eGFR changed from a -5.9% decrease to a 2.4% increase (p = 0.0098).
Our results indicated that statins stabilized the renal function of IgAN patients independent of their reduction of proteinuria.
[Show abstract][Hide abstract] ABSTRACT: Antineutrophil cytoplasmic autoantibody (ANCA) directed against myeloperoxidase (MPO), a diagnostic criterion in MPO-ANCA-associated vasculitis (MPO-AAV), does not always correlate with disease activity. Here, we detected autoantibodies against moesin, which was located on the surface of stimulated endothelial cells, in the serum of patients.
The anti-moesin autoantibody titer was evaluated by ELISA. Seventeen kinds of cytokines/chemokines were measured by a Bio-Plex system.
Serum creatinine in the anti-moesin autoantibody-positive group was higher than that in the negative group. Additionally, interferon (IFN)-γ, macrophage chemotactic peptide-1 (MCP-1), interleukin (IL)-2, IL-7, IL-12p70, IL-13, granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor were significantly higher in the positive group. Furthermore, IL-7 and IL-12p70 levels correlated with the anti-moesin autoantibody titer. Based on these findings and the binding of anti-moesin IgG to neutrophils and monocytes, we detected the secretion of cytokines/chemokines such as IFN-γ, MCP-1 and GM-CSF from these cells.
The anti-moesin autoantibody existed in the serum of patients with MPO-AAV and was associated with the production of inflammatory cytokines/chemokines targeting neutrophils with a cytoplasmic profile, which suggests that the anti-moesin autoantibody has the possibility to be a novel autoantibody developing vasculitis via neutrophil and endothelial cell activation.
Preview · Article · Dec 2013 · Nephrology Dialysis Transplantation
[Show abstract][Hide abstract] ABSTRACT: Objective:
IgA nephropathy (IgAN) is widely regarded as a slowly progressive disease. However, a minor population of patients present with a rapidly progressive form of glomerulonephritis (RPGN).
We studied 25 cases of IgAN who presented with RPGN. The laboratory data, histology, and five-year prognosis after diagnostic renal biopsy were evaluated. We compared the data of these patients with those of 495 patients with the non-RPGN type. In addition, we divided the patients with the RPGN type of IgAN into a group with reduced renal function and a group with maintained renal function, and compared the data between the two groups.
In the 'RPGN type', the serum creatinine levels and a 24-hour urinary protein excretion were significantly higher than in the non-RPGN type. Histological examinations showed that the rates of endocapillary hypercellularity and tubular atrophy/interstitial fibrosis were significantly higher in the patients with the RPGN type. In the comparison between the groups with reduced and maintained renal functions, the former group exhibited higher levels of proteinuria, serum creatinine and crescent formation than the latter group.
The RPGN type of IgAN was significantly worse in terms of the renal survival rate at five years than the non-RPGN type. Intensive and active treatments are necessary for this minor population, according to the guideline for the management of RPGN.
No preview · Article · Nov 2013 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The Vasculitis Damage Index (VDI) is used to define the degree of damage occurring in patients with systemic vasculitis. We conducted a retrospective study of 30 patients with microscopic polyangiitis (MPA) and renal-limited vasculitis (RLV).
The clinical data and VDI of the 30 patients enrolled in the study were collected and assessed for a period of 5 years.
The VDI score, which was 2.5 at 1 year after the initial diagnosis, increased gradually to 4.3 at 5 years post-diagnosis. The degrees of musculoskeletal and ocular damage significantly increased during the 5-year period (p = 0.001 and p = 0.002, respectively). The most frequent damage items in the VDI were cataract (13 %), hypertension (12 %), diabetes mellitus (9 %), and osteoporosis (6 %). The VDI score was significantly higher in the groups of patients who showed relapse or MPA than in the groups of patients who did not show relapse or RLV at 5 years (p = 0.02 and p = 0.03, respectively). In addition, a significant correlation was found between the VDI score at 5 years and the Birmingham Vasculitis Activity Score at diagnosis (p = 0.04, r = 0.4).
The VDI was found to be a useful tool for determining the severity of damage caused by disease and the effects of treatment. The individual contributions of the VDI items may also be applied to treatment decisions.
No preview · Article · Jan 2013 · Modern Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Objective:
The beneficial effects of renin-angiotensin-aldosterone system inhibitors (RASI) and the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on IgA nephropathy (IgAN) have been reported. However, it is unknown whether these agents have any synergistic interactions.
We divided 38 IgAN patients into two groups: an EPA group (n=18) treated with RASI plus EPA and a DILAZEP group (n=20) treated with RASI plus dilazep dihydrochloride. We analyzed the clinical and histological background of each patient, any relevant clinical findings obtained one year after treatment and any factors significantly related to decreases in proteinuria.
The clinical findings were largely similar between the groups, except for body mass index (24.9±4.5 in the EPA group vs. 21.4±2.1 in the DILAZEP group, p=0.0041) and total cholesterol (median: 206.0 vs. 177.5 mg/dL, p=0.0493). The histological findings, evaluated according to the Oxford classification, were also similar between the groups. At one year after treatment, the EPA group demonstrated a significantly decreased mean blood pressure (from 94.7±9.0 to 86.4±7.2 mmHg, p=0.0007) and a significantly decreased median level of proteinuria (from 0.80 to 0.41 g/g creatinine, p<0.001). In the DILAZEP group, the mean blood pressure significantly decreased (from 95.2±13.2 to 88.1±7.7 mmHg, p<0.001) without any significant decrease in the median level of proteinuria (from 0.88 to 0.60 g/g creatinine). According to a multivariate logistic analysis, EPA was found to be the only independent factor related to decreases in proteinuria (odds ratio = 5.073, 95% CI: 1.18-26.7, p=0.0285).
We conclude that EPA accelerates the effects of RASI and thus decreases the proteinuria observed in patients with IgAN.
No preview · Article · Jan 2013 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: The prognostic value of renal biopsy in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is widely recognized; however, there is no consensus regarding its pathological classification. Berden et al. proposed a new classification of glomerulonephritis in ANCA-associated vasculitis (AAV) categorized into focal, crescentic, mixed, and sclerotic classes and showed its prognostic value in 100 international multicenter cohorts for 1- and 5-year renal outcomes. In order to evaluate whether this new classification has predictive value and reproducibility in Japanese AAV cases, 87 cohorts with only microscopic polyangiitis in 3 limited centers in Japan were analyzed. In addition, those from Japan, Europe (Berden's cohorts) and China were compared in a recent report.
Full-text · Article · Dec 2012 · Clinical and Experimental Nephrology
[Show abstract][Hide abstract] ABSTRACT: Background
Steroid-dependent minimal-change nephrotic syndrome (MCNS) requires administration of prolonged courses of prednisolone (PSL); therefore, a paradigm shift from such toxic 'non-specific' therapies to selective immunomodulating regimens is necessary for these cases.Methods
To assess the therapeutic effects of rituximab (an anti-CD20 antibody) in adult patients with steroid-dependent MCNS, we performed a prospective trial of the effects of a single dose of rituximab administered twice at an interval of 6 months in 25 MCNS patients. We evaluated the biochemical parameters and compared the clinical findings between the 12-month period before and 12-month period after the first rituximab infusion.ResultsA significant reduction in the number of relapses and the total dose and the maintenance dose of PSL administered was observed during the 12-month period after the first rituximab infusion when compared with the findings during the 12-month period before the first rituximab infusion [25 (100%) versus 4 (16%), P < 0.001; 8.2 versus 3.3 g, P < 0.001; 26.4 mg/day at baseline versus 1.1 mg/day at 12-month, P < 0.0001]. Complete remission was achieved/maintained in all patients undergoing B-cell depletion. Four of 17 patients with B-cell repletion developed relapse.Conclusions
Our results revealed that rituximab therapy was associated with a reduction in the number of relapses and in the total dose of PSL needed. Therefore, rituximab appears to be a useful therapeutic agent for adult patients with steroid-dependent MCNS. These results suggest that this treatment is rational and should be considered as an important option in the management of adult patients with steroid-dependent MCNS.
No preview · Article · Dec 2012 · Nephrology Dialysis Transplantation
[Show abstract][Hide abstract] ABSTRACT: Background:
Pathogenesis and clinical prognosis of membranoproliferative glomerulonephritis (MPGN) has not yet been established.
We conducted a retrospective study of 41 patients with MPGN (type I and III) and examined the renal survival. In addition, factors contributing to survival time were analyzed.
Fourteen patients (34 %) were classified into the renal death group. Patients with nephrotic syndrome and positive C1q staining of glomerular deposits showed a particularly poor prognosis. Significantly higher frequency of nephrotic syndrome and higher urinary protein excretion were observed in the renal death group (p = 0.0002, p = 0.0002) than in the renal survival group. The intensity of C1q staining was positively correlated with the severity of the proteinuria (p = 0.004). Factors that influenced the survival time were positive C1q staining of glomerular deposits (p = 0.003), presence of nephrotic syndrome (p = 0.004), serum albumin (p = 0.02), and proteinuria (p = 0.04).
C1q staining in glomerular deposits and nephrotic syndrome were important factors influencing the prognosis and outcome in MPGN patients. C1q deposition may play a key role in the pathogenesis of MPGN, as evidenced by numerous observations, such as induction of proteinuria.
No preview · Article · Jul 2012 · Clinical and Experimental Nephrology