Severe leukocytopenia due to copper deficiency induced by zinc supplementation in a patient on peritoneal dialysis: a case report.

Zinc deficiency is one cause of anemia. However, it has been reported that some patients who were treated with zinc supplementation to resolve this anemia subsequently experienced copper deficiency, which lead to continued anemia, as well as leukocytopenia and other symptoms. However, only two patients with copper deficiency induced by zinc supplementation undergoing peritoneal dialysis have been reported. Here, we report the case of a 59 year-old man with copper deficiency after zinc supplementation undergoing peritoneal dialysis (PD). He took meals only once a day and drank about 750 mL/day of wine every day. He had been receiving zinc supplementation for 4 months. He was diagnosed with severe leukocytopenia and worsening anemia at a planned outpatient visit; in addition, his copper levels had markedly decreased. Thus, zinc supplementation was discontinued, and the patient was instructed to take cocoa for copper supplementation. Because of severe leukocytopenia, he was admitted to our hospital, and granulocyte colony-stimulating factor was administered. Red blood cell transfusions were performed for anemia. After discontinuing zinc supplementation, his white blood cell count and hemoglobin levels improved.To avoid Cu deficiency, patients' dietary history should be checked in detail and Cu should be monitored carefully when Zn is supplemented in patients undergoing PD.

A Formula for the Estimation of 24-Hour Urinary Creatinine Excretion: A Derivation and Validation Study.

OBJECTIVE: Twenty-four-hour urinary creatinine (Cr) excretion (24h-uCr) is the basis of Cr clearance and urinary protein-Cr ratio, and it is related to frailty, worsening kidney function, and mortality in patients with chronic kidney disease. Although subjects with lower estimated glomerular filtration rate (eGFR) tend to have lower 24h-uCr, previous formulae for the estimation of 24h-uCr did not include Cr as a predictor. METHODS: This retrospective study included patients admitted to the Department of Nephrology at our hospital (derivation cohort and validation cohort: patients admitted between April 2016 and March 2020). The prediction formula of 24h-uCr was calculated using a multivariate linear regression model with the bootstrap method. Age, height, weight, sex, Cr, and cystatin C were used as predictors. RESULTS: The derivation and validation cohorts included 187 and 63 patients, respectively. The characteristics of the derivation and validation cohorts were as follows: age 73 (61-79.5) years and 70 (58.5-79) years; males, 61.5% and 60.3%; eGFRCr 27.0 (13.7-48.6) mL/min/1.73 m2 and 26.3 (14.0-51.5) mL/min/1.73 m2; and 24-hour urinary protein excretion 0.79 (0.17-2.12) g/day and 1.08 (0.26-2.55) g/day, respectively. Seven prediction formulae were derived. In all models, the Pearson's correlation coefficient was relatively high and statistically significant. However, previous models tended to overestimate the 24h-uCr. Furthermore, the predicted 24h-uCr calculated by the models that do not include Cr as a predictor fluctuates depending on the eGFRCr. CONCLUSION: The best formula for predicting 24h-uCr (mg/day) in a wide range of eGFR populations is a Cr-containing formula: [-9.04 × age (years) + 8.03 × weight (kg) + 0.66 × height (cm) + 188.59 (if male) - 32.11 × Cr (mg/dL) + 779.14].

IFI27 Is a Useful Genetic Marker for Diagnosis of Immunoglobulin A Nephropathy and Membranous Nephropathy Using Peripheral Blood.

Diagnosis of chronic glomerulonephritis (CGN) depends primarily on renal biopsy, which is expensive and requires hospitalization, creating a demand for noninvasive diagnostic method for this disease. We used DNA microarray analysis to search for genes whose expression levels in peripheral blood mononuclear cells (PBMCs) could distinguish between patients with CGN and healthy volunteers (HVs). We selected immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) as typical forms of CGN. The mRNA level of the gene encoding interferon (IFN)-alpha-inducible protein 27, IFI27, which is preferentially expressed in podocytes of glomeruli, was lower in PBMCs of IgAN and MN patients than in those of HVs. This result was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Moreover, qRT-PCR analysis revealed that the IFI27 mRNA level was reduced in PBMCs of patients with other types of chronic glomerulonephritis. IFI27 immunohistochemical staining of biopsied specimens also confirmed reduced expression of IFI27 protein in IgAN and MN patients. Based on these results, we propose that IFI27 could serve as a noninvasive diagnostic marker for CGNs using peripheral blood.

Minimal Change Nephrotic Syndrome Which Was Most Likely Caused by Chronic Sinusitis.

A 33-year-old Japanese man was admitted with severe edema, and a renal biopsy confirmed minimal change nephrotic syndrome (MCNS). CT revealed his severe chronic sinusitis, and he first received antimicrobial therapy, which resulted in decreased proteinuria. The surgical operation for sinusitis resulted in the complete disappearance of proteinuria without corticosteroid or immunosuppressant therapy within one week. MCNS may be triggered by infection, but there are no previously reported cases of MCNS that is completely remitted by infection control alone. Therefore, we herein report the first case of MCNS that attained complete remission following therapy for chronic sinusitis alone, which suggests a strong etiology of chronic sinusitis for MCNS.

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

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

Deficiency of N-acetylgalactosamine in O-linked oligosaccharides of IgA is a novel biologic marker for Crohn's disease.

BACKGROUND: Ideal biomarkers are required to be developed for the diagnosis and prediction of the treatment of inflammatory bowel disease (IBD). We have reported that alteration of N-linked oligosaccharides of immunoglobulin (Ig) G is a novel diagnostic marker of IBD. Oligosaccharide alterations of IgA, however, have not been investigated in IBD patients. METHODS: N- and O-linked oligosaccharides of serum IgA purified from 32 patients with Crohn's disease (CD), 30 patients with ulcerative colitis (UC), and 30 healthy volunteers (HV) were analyzed with high-performance liquid chromatography and mass spectrometry. Enzymes related to oligosaccharide attachment were investigated. RESULTS: N-linked oligosaccharides of IgA were not different between IBD and HV. In contrast, the number of N-acetylgalactosamines per hinge glycopeptide (GalNAc/HP) in the O-linked oligosaccharides of IgA was significantly decreased in patients with CD compared with UC and HV. GalNAc/HP had high sensitivity and specificity for discriminating between CD and HV based on receiver operating characteristic analysis. Lower GalNAc/HP was associated with more severe disease activity of CD. Changes in GalNAc/HP levels in 6 weeks after treatment with infliximab were associated with the clinical activity of CD at 30 weeks. GalNAc transferase expression of naïve B cells and extent of GalNAc attachment in IgA were significantly decreased by interleukin-21 in vitro. CONCLUSIONS: The number of GalNAc attached in the IgA O-linked glycans of CD patients was significantly decreased, and strongly correlated with the clinical activity. Alterations of GalNAc attachment in IgA could be useful as a novel diagnostic and prognostic marker of CD.

Self-reported sleep duration and prediction of proteinuria: a retrospective cohort study.

BACKGROUND: Although multiple studies have shown that sleep duration is a predictor of cardiovascular diseases and mortality, few studies have reported an association between sleep duration and chronic kidney disease. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 6,834 employees of Osaka University aged 20-65 years who visited Osaka University Healthcare Center for their mandatory annual health examinations between April 2006 and March 2010 and did not have estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), proteinuria, or treatment for self-reported kidney disease. PREDICTOR: Self-reported questionnaires about life style, including sleep duration, and blood and urine testing at the first examinations during the study period. An association between sleep duration and outcome was assessed using multivariate Poisson regression models adjusting for clinically relevant factors. OUTCOME: Time to the development of proteinuria defined as 1+ or higher by dipstick test. RESULTS: Self-reported baseline sleep duration was 6.0 ± 0.9 hours, which reflected the mean sleep duration during a median of 2.5 (25th-75th percentile, 1.4-3.9) years of the observational period. Development of proteinuria was observed in 550 employees (8.0%). A multivariate Poisson regression model clarified that shorter sleep duration, especially 5 or fewer hours, was associated with the development of proteinuria in a stepwise fashion (vs 7 hours; incidence rate ratios of 1.07 [95% CI, 0.87-1.33; P = 0.5], 1.28 [95% CI, 1.00-1.62; P = 0.05], and 1.72 [95% CI, 1.16-2.53; P = 0.007] for 6, 5, and ≤4 hours, respectively), along with younger age, heavier current smoking, trace urinary protein by dipstick test, higher eGFR, higher serum hemoglobin A(1c) level, and current treatment for heart disease. A stepwise association between shorter sleep duration and the development of proteinuria also was verified in 4,061 employees who did not work the night shift. LIMITATIONS: Self-reported sleep duration might be biased. Results in a single center should be confirmed in the larger cohort including different occupations. CONCLUSION: Short sleep duration, especially 5 or fewer hours, was a predictor of proteinuria.

Gene polymorphisms contributing to hypertension in immunoglobulin A nephropathy.

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

Urinary type IV collagen in nondiabetic kidney disease.

BACKGROUND: Type IV collagen is one of the major components of basement membrane. In diabetic nephropathy, it is already known that urinary excretion of type IV collagen increases with the disease progression. However, in nondiabetic kidney disease, urinary type IV collagen (u-IVc) levels have not been extensively investigated. The aim of this study was to evaluate u-IVc levels in various nephropathies except diabetic nephropathy. METHODS: u-IVc levels were measured cross-sectionally from 527 biopsy-proven nondiabetic renal disease patients at tertiary care hospitals by one-step sandwich enzyme immunoassay. RESULTS: On simple regression analyses, u-IVc levels had positive correlation with age, blood pressure, urinary protein (u-Prot), urinary ß(2) microglobulin, urinary N-acetyl-ß-D-glucosaminidase, HbA(1)c, and selectivity index (SI), while u-IVc had negative correlation with eGFR and serum albumin. Multiple regression analyses revealed that u-IVc was positively correlated with u-Prot, HbA(1)c and SI. Among biopsy-proven nondiabetic nephropathies, elevation of u-IVc was distinctively observed in membranous nephropathy and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. CONCLUSION: u-IVc levels were elevated with the increase in u-Prot, HbA(1)c and SI. In addition, among nondiabetic kidney disease, elevation of u-IVc was observed in patients with membranous nephropathy and ANCA, which might reflect the thickening of basement membrane or severe kidney damage.

Cigarette smoking and progression of IgA nephropathy.

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

Microarray analysis of tonsils in immunoglobulin A nephropathy patients.

BACKGROUND: Recently, combination of tonsillectomy and steroid pulse therapy was reported to be effective as the treatment of the immunoglobulin A nephropathy (IgAN). However, the gene expression difference between the tonsils in patients with IgAN and those in control patients is not established. METHODS: We performed tonsillectomy combined with steroid pulse as a treatment to IgAN, analyzed the gene expression in the tonsils (N=23) using microarray, compared with those with patients suffering from chronic tonsillitis (N=22). From some candidate genes related with IgAN, we confirmed the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptides 2 (APOBEC2) gene expression in the tonsil and we also analyzed its expression levels and clinical features. RESULTS: Up-regulated genes seem to be categorized into two groups. One group belongs to the muscle related genes which might be caused by structural differences. The other group includes the immune system-related genes, such as APOBEC2, CALB2, DUSP27, and CXCL11. APOBEC2 was positively stained in the epithelium and the peripheral region of the germinal center in both tonsils. APOBEC2 expression level was negatively related with serum igg level, but did not correlate with clinical course after tonsillectomy. CONCLUSION: We confirmed gene expression differences related with immune system and muscle structure. The APOBEC2 was confirmed to be elevated in the tonsils with IgAN patients, and the gene expression level was negatively related with serum igg level in overall patients. These results might be helpful to reveal the mechanism of IgAN.

Kidney repair using stem cells: myth or reality as a therapeutic option?

The kidney has been considered a highly terminally differentiated organ of the body, and its proliferative potential is low, with the result that it has been thought of as a most unlikely organ for regeneration. From the structural point of view, the kidney is elaborately composed of many cell types that function as a tissue unit and not as individual cells, which also makes it more difficult to regenerate. However, in clinical settings, the kidney does have regenerative potential as seen in the recovery from acute kidney injury. The role of bone marrow-derived mesenchymal stromal cells may mainly be to produce humoral factors accelerating regeneration. The origin, localization and role of kidney stem cells are under investigation. We also discuss potential applications of embryonic stem cells and induced pluripotent stem cells in kidney regeneration.

Kid-1 participates in regulating ERK phosphorylation as a part of the circadian clock output in rat kidney.

Circadian clock genes play a role for the regulation of cell cycle, but the factors connecting clock to cell cycle are not fully understood. We found that mRNA of Kid-1--a zinc-finger-type transcriptional repressor was localized to cortical and juxtamedullary segments of tubules but not to glomeruli in the rat kidney. Kid-1 mRNA showed robust circadian oscillation with a peak at ZT16. Under temporal restricted feeding, the phase of the oscillation shifted along with mRNAs of the clock genes--Per1 and Per2. The rhythm of S-phase in cell cycle disappeared in the kidney under the restricted feeding. The level of phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was rhythmic with a peak at ZT16 in the kidney. We found that knockdown and overexpression of Kid-1 in NRK52E (normal rat kidney epithelial) cells induced and reduced the phosphorylation of ERK1/2, respectively. The data suggest that clock-controlled Kid-1 regulates the cell cycle of proliferating renal tubular epithelial cells through ERK phosphorylation.

Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice.

OBJECTIVE: Obesity is recognized increasingly as a major risk factor for kidney disease. We reported previously that plasma adiponectin levels were decreased in obesity, and that adiponectin had defensive properties against type 2 diabetes and hypertension. In this study, we investigated the role of adiponectin for kidney disease in a subtotal nephrectomized mouse model. METHODS AND RESULTS: Subtotal (5/6) nephrectomy was performed in adiponectin-knockout (APN-KO) and wild-type (WT) mice. The procedure resulted in significant accumulation of adiponectin in glomeruli and interstitium in the remnant kidney. Urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis were significantly worse in APN-KO mice compared with WT mice. Intraglomerular macrophage infiltration and mRNA levels of vascular cell adhesion molecule (VCAM)-1, MCP-1, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, collagen type I/III, and NADPH oxidase components were significantly increased in KO mice compared with WT mice. Treatment of APN-KO mice with adenovirus-mediated adiponectin resulted in amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis and reduced the elevated levels of VCAM-1, MCP-1, TNF-alpha, TGF-beta1, collagen type I/III, and NADPH oxidase components mRNAs to the same levels as those in WT mice. CONCLUSIONS: Adiponectin accumulates to the injured kidney, and prevents glomerular and tubulointerstitial injury through modulating inflammation and oxidative stress.

A case of Wegener's granulomatosis with pulmonary bleeding successfully treated with double filtration plasmapheresis (DFPP).

We report a case of a 41-year-old Japanese man who presented with rapidly progressive glomerulonephritis, chronic sinusitis, and positive cytoplasmic-antineutrophil cytoplasmic antibody (c-ANCA). Renal biopsy showed crescentic glomerulonephritis, and he was diagnosed as having Wegener's granulomatosis. During the clinical course, he suffered from pulmonary bleeding, and combination therapy of steroid, immunosuppressant, and double filtration plasmapheresis (DFPP) was started. He rapidly entered remission after assistance through DFPP, suggesting the potential efficacy of DFPP for Wegener's granulomatosis, especially with pulmonary bleeding.

Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury.

Fetal microchimerism indicates a mixture of cells of maternal and fetal origin seen in maternal tissues during and after pregnancy. Controversy exists about whether persistent fetal microchimerism is related with some autoimmune disorders occurring during and after pregnancy. In the current experiment, an animal model in which EGFP positive cells were taken as fetal-origin cells was designed to detect the fetal microchimerism in various maternal organs. Ethanol drinking and gentamicin injection were adopted to induce liver and kidney injury simultaneously. EGFP positive cells were engrafted not only in the maternal circulation and bone marrow, but also in the liver and kidney as hepatocytes and tubular cells, respectively. These results indicate that fetal cells are engrafted to maternal hematopoietic system without apparent injury and they also contribute to the repairing process of maternal liver and kidney.

Hematopoietic and nonhematopoietic potentials of Hoechst(low)/side population cells isolated from adult rat kidney.

BACKGROUND: Although the regenerative stem cell is expected to exist in many adult tissues, the cell contributing to the regeneration of the kidney remains unknown in its type and origin. METHODS: In this study, we isolated cells that show low stain with a DNA-binding dye Hoechst 33342 (Hoechst(low) cells) from adult rat kidney, and investigated their differentiation potentials. RESULTS: Hoechst(low) cells, generally termed side population cells, existed at a frequency of 0.03% to 0.1% in the cell suspension of the digested kidney. Analysis of the kidney-derived Hoechst(low) cells after bone marrow transplantation indicated that some of the cells were derived from bone marrow. When enhanced green fluorescent protein (EGFP)-labeled kidney-derived Hoechst(low) cells were intravenously transplanted into wild-type adult rats, EGFP(+) cells were not detected in the kidney, but EGFP(+) skeletal muscle, EGFP(+) hepatocytes and EGFP(+) bone marrow cells were observed. Even after the induction of the experimental glomerulonephritis and gentamicin-induced nephropathy that promote the differentiation of bone marrow-derived cells into repopulating mesangial cells and tubular component cells, respectively, EGFP(+) mesangial or tubular cells were not observed. Neither with an in vitro system, which we established to produce mesangial-like cells from crude bone marrow culture, did Hoechst(low) cells yield mesangial-like cells. CONCLUSION: These findings implicate that Hoechst(low) cells in the kidney may have potentials for hematopoietic and nonhematopoietic lineages, but are not stem cells for renal cells, especially mesangial and tubular cells.

Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin.

Renal proximal tubular cells activated by reabsorption of protein are thought to play significant roles in the progression of kidney diseases. It was hypothesized that the signal transducer and activator of transcription (STAT) proteins may be activated by proteinuria in proximal tubular cells. To test this hypothesis, murine proximal tubular cells were treated with albumin (30 mg/ml medium) for various lengths of time. The results showed that albumin could activate Stat1 and Stat5 within 15 min in proximal tubular cells. The activation of STATs was mediated mostly by Jak2 and required no protein synthesis. In addition, activation of Stat1 occurred even after neutralization of IFN-gamma. The activation of STATs was inhibited by N-acetyl-L-cysteine, a precursor of glutathione and a reactive oxygen species (ROS) scavenger, and fluorescence-activated cell sorter analysis showed upregulation of intracellular ROS after albumin overloading, suggesting that albumin per se could generate ROS in proximal tubular cells. The activation of STATs occurred by way of the ROS generating system, and especially through the membrane-bound NADPH oxidase system. Reduced activities of glutathione peroxidase and catalase could also be responsible for the accumulation of intracellular ROS. Hence, not only the ROS generating system, but also the ROS scavenging system may contribute to the induction of ROS by albumin. These findings support the hypothesis that proximal tubular cells are activated and generate ROS by reabsorption of abundant urinary proteins filtered through the glomerular capillaries, and as a consequence, various IFN-gamma-inducible proteins are synthesized through IFN-gamma-independent activation of STAT signaling.