Mechanical stretch down-regulates expression of the Smad6 gene in cultured rat mesangial cells.

BACKGROUND: Glomerular hypertension aggravates glomerular sclerosis by inducing growth factors, e.g., transforming growth factor-ß (TGF-ß) to mesangial matrix expansion. Smads are intracellular proteins that transmit signals from TGF-ß to nucleus, and Smads are also negatively regulated by inhibitory Smads (I-Smads), Smad6 and Smad7. However, little is known about the role of I-Smads in glomerular hypertension. We studied I-Smad expression in cultured mesangial cells subjected to mechanical stretch as an in vitro model of glomerular hypertension. METHODS: Rat mesangial cells were cultured under cyclic mechanical stretch conditions using the Flexercell Strain Unit. Phosphorylated Smad1 and Smad2 were determined by Western blots. The expression of Smad6 and Smad7 mRNAs was determined by Northern blots. Stretch-mediated I-Smad mRNAs of cells pre-treated with MAPK-ERK kinase inhibitor, U0126, were also determined. Localization of phospho-Smad1, Smad6 and Smad7 proteins in the glomerulus of Dahl salt-sensitive rats was determined by immunohistochemistry. RESULTS: Stretch stress increased phospho-Smad1 levels, and significantly decreased Smad6 mRNA to 32 % of control, and increased Smad7 mRNA to 136 % of control. U0126 significantly attenuated stretch-mediated decreases in Smad6 mRNA, but had no effect on stretch-mediated increases in Smad7 mRNA. Phospho-Smad1, Smad6 and Smad7 proteins were localized in podocytes and mesangial cells of Dahl rats. CONCLUSION: Mechanical stretch increases phospho-Smad1 levels and down-regulates Smad6 mRNA expression in mesangial cells. Stretch-mediated down-regulation of Smad6 is partially involved in ERK1/2 activation. These results indicate that glomerular hypertension might augment Smad1 signaling with concomitant attenuation of Smad6-mediated negative feedback.

Dietary Perilla seed oil supplement increases plasma omega-3 polyunsaturated fatty acids and ameliorates immunoglobulin A nephropathy in high immunoglobulin A strain of ddY mice.

BACKGROUND/AIMS: The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in the treatment of immunoglobulin A nephropathy (IgAN) have been reported. Perilla frutescens (Linn.) Britton var. frutescens is grown in Eastern Asia and its seed (perilla seed) is rich in α-linolenic acid, an n-3 PUFA. We investigated the antinephritic effects of perilla seed oil in a mouse model of IgAN. METHODS: Ten-week-old high IgA ddY mice were fed diets containing either perilla seed oil (PS group) or corn oil (C group, control). After 20 weeks, we compared body weight, blood pressure, serum creatinine levels, IgA levels, fatty acid composition, urinary protein excretion, mesangial matrix expansion, and glomerular transforming growth factor-ß1 mRNA expression between groups. RESULTS: Serum n-3 PUFA levels were higher in the PS group than the C group (p<0.001). Blood urea nitrogen levels were lower (p=0.0246) and urinary protein excretion was reduced (p=0.0198) in the PS group. Mesangial matrix expansion (p=0.0063) and glomerular transforming growth factor-ß1 mRNA expression (p=0.0291) were suppressed in the PS group. No significant differences between groups were found in body weight, blood pressure, serum IgA, and creatinine levels. CONCLUSIONS: Dietary perilla seed oil supplement could suppress the progression of IgAN.

Common variation in GPC5 is associated with acquired nephrotic syndrome.

Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P(rec)) = 6.0 × 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.

Skin autofluorescence is associated with renal function and cardiovascular diseases in pre-dialysis chronic kidney disease patients.

BACKGROUND: Tissue accumulation of advanced glycation end-products (AGE) is thought to be a contributing factor to the progression of cardiovascular disease (CVD). Skin autofluorescence, a non-invasive measure of AGE accumulation using autofluorescence of the skin under ultraviolet light, has shown associations with CVD in haemodialysis patients. The present study aimed to evaluate relationships of skin autofluorescence to renal function as well as CVD in pre-dialysis patients with chronic kidney disease (CKD). METHODS: Subjects in this cross-sectional analysis comprised 304 pre-dialysis CKD patients [median age, 62.0 years; median estimated glomerular filtration rate (eGFR), 54.3 mL/min/1.73 m(2); diabetes, n = 81 (26.6%)]. AGE accumulation in skin was assessed by skin autofluorescence using an autofluorescence reader. Relationships between skin autofluorescence, eGFR, CVD history and other parameters were evaluated. RESULTS: Skin autofluorescence correlated negatively with eGFR (r = -0.42, P < 0.01) and increased as CKD stage advanced. Multiple regression analysis revealed significant correlations of skin autofluorescence with age, presence of diabetes, eGFR and CVD history in CKD patients (R(2) = 30%). Age, male gender, smoking history, skin autofluorescence and eGFR were significantly correlated with CVD history, and multiple logistic regression analysis identified age [odds ratio (OR), 1.09; 95% confidence interval (CI), 1.03-1.15; P < 0.01], history of smoking (OR, 6.50; 95%CI, 1.94-21.83; P < 0.01) and skin autofluorescence (OR, 3.74; 95%CI, 1.54-9.24; P < 0.01) as independent factors. CONCLUSIONS: Tissue AGE accumulation measured as skin autofluorescence increased as GFR decreased and was related to CVD history in CKD patients. Non-invasive autofluorescence readers may provide potential markers for clinical risk assessment in pre-dialysis CKD patients.

Relationship of skin autofluorescence to cardiovascular disease in Japanese hemodialysis patients.

Advanced glycation end products (AGE) are significantly increased in end-stage renal disease patients and it has been suggested that AGE accumulation is related to the progression of cardiovascular disease. An autofluorescence reader non-invasively assesses AGE accumulation using skin autofluorescence under ultraviolet light. Skin autofluorescence has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. The aim of this study was to assess whether skin autofluorescence in Japanese hemodialysis patients is related to the presence of cardiovascular disease. In this cross-sectional study, patients on maintenance hemodialysis (N = 128; 59 men, 69 women) were included. AGE accumulation was assessed by skin autofluorescence using an autofluorescence reader. Associations between skin autofluorescence, cardiovascular disease, and other parameters were studied. Skin autofluorescence correlated with age (r = 0.32, P < 0.01), diabetes (r = 0.21, P = 0.02), carotid intima-media thickness (IMT) (r = 0.23, P = 0.02), high-sensitivity C-reactive protein (hsCRP) (r = 0.20, P = 0.03), and plasma pentosidine (r = 0.20, P = 0.03). Each parameter was compared in patients with and without cardiovascular disease; the gender distribution, age, carotid IMT, high-density lipoprotein cholesterol, hsCRP, and skin autofluorescence were significantly related to the presence of cardiovascular disease. Multiple logistic regression analysis identified carotid IMT (OR 6.76), hsCRP (OR 1.41), and skin autofluorescence (OR 2.29) as significant factors for the presence of cardiovascular disease. Increased skin autofluorescence was related to the presence of cardiovascular disease in Asian (non-Caucasian) hemodialysis patients, and therefore an autofluorescence reader might have the potential to be a useful assessment of cardiovascular risk in these patients.

Genetical, histological, and clinical characteristics of IgA-negative mesangioproliferative glomerulopathy.

BACKGROUND: Mesangioproliferative glomerulopathy (MesPGN) is a well-defined pathohistological entity. However, the clinical characteristics and prognosis have not been fully established in patients without immunoglobulin (Ig)A (N-IgAN) in contrast to patients with IgA nephropathy (IgAN). METHODS: A total of 837 consecutive patients underwent renal biopsies. Among them, 465 patients were diagnosed with MesPGN by light microscopy. With immunofluorescent study and electron microscopy (EM), 344 were diagnosed as having IgAN. Among the rest, 84 patients who had no immunofluorescence evidence of IgA and no deposits in EM were defined as N-IgAN. We compared the clinical characteristics, histological findings, and genotypes of the angiotensin-converting enzyme (ACE) gene and plasminogen activator inhibitor-1 gene between IgAN and N-IgAN patients. RESULTS: Urinary protein excretion and the degree of hematuria were significantly lower in N-IgAN than IgAN patients (0.50 vs. 0.82 g/day; P = 0.01), (1.33 vs. 2.50; P < 0.001, respectively). Creatinine clearance was higher in N-IgAN than IgAN patients (89.4 vs. 74.4 ml/min; P < 0.001). Histopathologically, N-IgAN patients had significantly less advanced glomerular and tubulointerstitial lesions than IgAN patients. Pathological grades in patients with untreated IgAN were more advanced in a time-dependent manner, whereas there was no relationship between histological grades and time of illness in N-IgAN patients. Frequency of the DD genotype of the ACE gene was significantly lower in N-IgAN (DD/ID+II = 8/76) than IgAN (24/90) patients. CONCLUSIONS: IgA-negative MesPGN is a distinct type of glomerulopathy with a benign renal prognosis. Insertion/deletion polymorphisms of the ACE gene may play some role in the genesis and progression of MesPGN.

Lupus nephritis with podocytic infolding and intramembranous microstructures.

We describe a 24-year-old woman with a distinctive glomerular lesion. She presented with nephrotic syndrome and the diagnosis of systemic lupus erythematosus was made on the basis of laboratory and clinical findings. Renal biopsy showed a bubbling appearance of the glomerular capillary wall indicating lupus nephritis class V. On an electron microscopy, the glomerular basement membrane (GBM) was irregularly thickened and contained abundant vesicular and microtubular bodies. In addition, there were many epithelial foot processes infolding into the GBM. A few small deposits were observed beneath the foot processes and around the vesicular and microtubular bodies. Although the clinicopathological significance of podocytic infolding has not been fully elucidated, it may be a novel morphological entity in the glomerulonephritides.

Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression.

Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.

Differential effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneously hypertensive rats.

The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.

Risk factors for bleeding complications in percutaneous renal biopsy.

BACKGROUND: Among the complications in percutaneous renal biopsy, bleeding is the most frequent and sometimes becomes fatal. METHODS: We prospectively studied 394 consecutive percutaneous renal biopsies in 359 patients (male/female = 188/171). The mean age of the patients was 44.0 +/- 17.2 years. Percutaneous renal biopsies were performed on native kidneys under direct visualization by ultrasound, using an automated spring-loaded biopsy device and a 16-cm 18 G needle. RESULTS: The most common complication was hematoma (n = 149, 37.8%). "De novo macrohematuria" was observed in 29 patients (7.4%). Other complications included pain (n = 27, 6.9%), loss of blood (n = 17, 4.3%), and renal dysfunction (increase of serum creatinine more than 0.2 mg/dl, n = 9, 2.2%). Although there were no severe complications such as loss of blood requiring a blood transfusion, loss of kidney function, or death, 10 patients had an extended rest period in bed because of moderate complications. Hypertension and amyloidosis had significant influence on the complications. CONCLUSIONS: For those who are clinically suspected of having amyloidosis or hypertension, more careful biopsy procedures and observations are necessary.

Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy.

BACKGROUND: In diabetic nephropathy (DN) small vessels are frequently observed around the glomerular vascular pole in addition to normal afferent and efferent arterioles; this is regarded as neovascularization . Because vascular endothelial growth factor (VEGF) promotes vascular generation, the authors investigated the relationship between glomerular VEGF gene expression and structural glomerular changes in the early stage of human DN. METHODS: Kidney specimens were obtained from 18 type 2 DN patients by open renal biopsy. Additional vessels were distinguished by light microscopy as either afferent or efferent arterioles. Glomerular VEGF messenger RNA expression was determined by using in situ hybridization. The mesangial matrix area was quantified, and the ratio of the mesangial matrix area to the whole glomerular area was calculated to determine the mesangial matrix index (MMI). RESULTS: There were significantly more glomeruli with extra vessels in DN than in normal kidneys. The degree of neovascularization was significantly increased in DN and correlated with the magnitude of VEGF messenger RNA expression (r 2 = 0.46, P = 0.010) and MMI (r 2 = 0.45, P = 0.0093). CONCLUSION: These findings suggest that glomerular VEGF may be involved in structural changes in human DN at an early stage.

Effects of salt loading on blood pressure in mice lacking the prostanoid receptor gene.

BACKGROUND: This study examined whether targeted disruption of the genes for the prostacyclin receptor (IP) or the thromboxane A2 receptor (TP) confers a susceptibility to salt-dependent hypertension. METHODS AND RESULTS: Eight female IP- or TP-deficient mice were examined. Baseline systolic blood pressure (SBP) did not differ between TP(-/-) and TP(+/+), but was significantly lower in the IP(-/-) group than in the IP(+/+). With a high salt diet, SBP in IP(-/-) gradually increased. In contrast, SBP in the IP(+/+), TP(-/-), or TP(+/+) groups remained unchanged. CONCLUSIONS: The prostacyclin receptor may participate in the maintenance of baseline BP. With salt loading, BP adaptation may take place, at least in part, via IP mediated signals.

Elevation of serum soluble E- and P-selectin in patients with hypertension is reversed by benidipine, a long-acting calcium channel blocker.

Hypertension is a major risk factor for atherosclerotic cardiovascular disease. Selectins, cell-surface adhesion molecules involved in leukocyte rolling and attachment to the vascular endothelium, play a role in the initiation of atherosclerosis. We investigated whether or not serum levels of soluble adhesion molecules are elevated in patients with essential hypertension (EH) and examined whether antihypertensive therapy lowers such levels. Twenty-one patients who had untreated mild to moderate EH without diabetes mellitus, hyperlipidemia, or obesity were recruited at a clinic for hypertensive patients. Blood pressure was measured, and the serum levels of soluble E-selectin, P-selectin, L-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular-cell adhesion molecule 1 (VCAM-1) were determined by enzyme-linked immunosorbent assays before and after 12, 24, and 53 weeks of antihypertensive treatment with benidipine, a long-acting calcium channel blocker, given at a dose of 6 mg/day for 53 weeks. As a control, 21 age- and sex-matched patients without hypertension were studied. Serum E- and P-selectin levels were significantly higher in the subjects with EH than in the controls (p < 0.01). There were no differences in serum levels of soluble L-selectin, VCAM-1, or ICAM-1 levels between the patients with EH and the controls. Treatment with benidipine decreased the elevated blood pressure over a 53-week study period (mean blood pressure: 119.8 +/- 6.5 mmHg at baseline, 101.0 +/- 5.9 mmHg at 12 weeks, 98.6 +/- 7.3 mmHg at 24 weeks, and 93.9 +/- 5.5 mmHg at 53 weeks). Serum levels of soluble E- and P-selectin decreased after the initiation of benidipine treatment and correlated with diastolic blood pressure. Serum levels of soluble L-selectin, VCAM-1, and ICAM-1 did not change significantly during the period of benidipine treatment. Benidipine treatment reduced the content of P-selectin in the platelets from patients with EH, as determined by Western blot analysis. In conclusion, decreased blood pressure may reduce the rate of progression of atherosclerosis by affecting the expression of E- and P-selectin in the endothelium, the platelets, or both. Benidipine may be protective against vascular damage in people with hypertension, not only by lowering blood pressure, but also by inhibiting the expression of selectins.

Multiple endocrine neoplasia type 1 in end-stage renal failure.

A 59-year-old woman with chronic renal failure due to type 2 diabetes mellitus (DM) is presented. Her father and a brother had a history of brain tumor. Her blood urea nitrogen and serum creatinine levels were 102 mg/dl and 4.5 mg/dl, respectively. Her serum Ca(2+) and Pi were within the normal range (9.4 mg/dl and 5.4 mg/dl, respectively). Her intact parathyroid hormone (PTH) level was 1 730 000 pg/ml. A (99m)Tc-methoxy-isobutylisonitrile scintigraphy showed high uptake in three parathyroid glands. A magnetic resonance image showed microadenoma in the pituitary gland. The serum gastrin level was high. Genetic examination revealed a mutation of the MEN1 gene (894-9 G --> A). From these findings, she was diagnosed with multiple endocrine neoplasia (MEN) type 1. Subsequently, a parathyroidectomy was performed successfully, a parathyroid gland was transplanted to her right forearm, and her serum Ca(2+) level was controlled at 8.5-9.0 mg/dl. It is very important to identify MEN1 if an end-stage renal disease (ESRD) patient has hyperparathyroidism with multigland involvement. Examination of the MEN1 gene may be valuable to make an accurate diagnosis and choose the appropriate therapy in some ESRD patients with hyperparathyroidism.

Rapid change of glucose concentration promotes mesangial cell proliferation via VEGF: inhibitory effects of thiazolidinedione.

Diabetic nephropathy is a common complication in diabetes mellitus (DM). Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy, however, the mechanism has not been elucidated. We hypothesized that VEGF participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy through its effect on VEGF. Increased VEGF expression was demonstrated in the glomeruli of DM rats and rat mesangial cells (RMC) incubated with high medium glucose. It was also demonstrated that VEGF promoted mesangial cell proliferation, which was inhibited by TZD. It was shown that a rapid fall and rise of ambient glucose concentration induces more VEGF production and cell proliferation in RMC than in cells with continuously high glucose medium, which was also inhibited by TZD. Prostaglandin J2 and protein C kinase inhibitors significantly inhibited [3H]thymidine incorporation in RMC incubated with VEGF, which was inhibited by TZD. These findings indicate that a rapid change of glucose concentration promotes RMC proliferation by the increased production of VEGF. TZD has an inhibitory action through, at least in part, PPAR-gamma.

Steroid therapy reduces mesangial matrix accumulation in advanced IgA nephropathy.

BACKGROUND: Steroid therapy for IgA nephropathy (IgAN) has been reported to ameliorate the long-term prognosis of IgAN, but its mode of action has not been fully elucidated. In this study, we examined the effect of steroids on glomerular morphological changes in IgAN. METHODS: We examined 16 patients with biopsy-proven IgAN (male/female =11/5, mean age 32.1 years) who were divided into prognosis groups according to criteria set by the Japanese Society of Nephrology. Initially, they received a loading dose of steroids, followed by a daily dose of 10-15 mg prednisolone. After 12 months, they underwent a second biopsy, and their histological and clinical features were examined. RESULTS: Before and after therapy, systolic blood pressure, diastolic blood pressure, serum creatinine and creatinine clearance all remained unchanged. However, urinary protein excretion decreased dramatically, from 1.6+/-1.7 to 0.4+/-0.2 g/day (P<0.005). Furthermore, computerized imaging revealed a significant reduction of the mesangial matrix index (MMI) from 14.5+/-5.2 to 9.5+/-3.6% (P<0.001). The numbers of sclerosing glomeruli did not change. CONCLUSIONS: Steroid therapy reduces mesangial matrix accumulation and reduces urinary protein excretion in advanced IgAN.

Fabry disease with few clinical signs and symptoms.

We describe a 25-year-old man with Fabry disease who remained undiagnosed until progressive renal involvement had begun, because of few clinical signs or symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria and normal renal function. Renal biopsy revealed focal and segmental glomerular sclerosis with vacuolated podocytes. Electron microscopy demonstrated characteristic lamellated bodies. Alpha-galactosidase A (alpha-galA) activity was markedly decreased. Early diagnosis of Fabry disease is becoming important because of the prospect of recombinant alpha-galA replacement therapy. Careful history taking, physical examinations, and renal histology with electron microscopy are essential for the diagnosis in the course of the disease.

The product of duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointerstitial damage in IgA nephropathy.

BACKGROUND/AIMS: IgA nephropathy (IgAN) is one of the major causes for chronic renal failure (CRF). Presence of massive proteinuria, hypertension, increased serum creatinine level and sclerotic histopathological changes of the glomerulus are known to be determinants for the progression of CRF. However, the relationships between duration of proteinuria/hematuria and histopathological changes, which may be correlated with the renal prognosis, have not been clarified. METHODS: A cross-sectional, univariate analysis of clinical parameters on the four glomerular and three tubulointerstitial histopathological grades in 57 untreated biopsy-proven IgAN patients (M/F = 32/25) was performed. RESULTS: The age at the time of renal biopsy (35.2 +/- 13.0 years; mean +/- SD), average duration of proteinuria (5.3 +/- 5.8 years), mean urinary protein excretion (0.99 +/- 1.22 g/day), serum creatinine (Cr 0.97 +/- 0.28 mg/dl), Cr clearance (Ccr 75.5 +/- 29.4 ml/min), and blood urea nitrogen (BUN 15.4 +/- 3.9 mg/dl) were well correlated with both histopathological grades. The product of duration (years) and urinary protein excretion (g/day) at the time of renal biopsy was more significantly correlated with glomerular and tubulointerstitial histopathological grades and serum Cr. CONCLUSION: The natural course of IgAN is steadily progressive depending on the duration and amount of proteinuria. The product of these two factors (proteinuria index) may be a useful predictor for glomerular and interstitial histopathological changes and the fate of renal function in IgAN.