Resolution of proteinuria after transarterial embolization of aberrant renal artery in a patient with focal segmental glomerulosclerosis.

A 24-year-old man was admitted to our hospital for persistent proteinuria. He was born with a low birth weight but had grown up uneventful until the age of 20 when he was found to have proteinuria. Because his body mass index was 30.9 kg/m2 at that time, he was diagnosed as obesity-related nephropathy. However, weight reduction and administration of ACE inhibitor were minimally effective for the amelioration of proteinuria. Ultrasound-guided percutaneous renal biopsy at the lower pole of right kidney was performed. As serious bleeding occurred from the right aberrant renal artery soon after biopsy, he was treated with transarterial embolization (TAE). The day after TAE, proteinuria completely disappeared. Renal biopsy showed benign nephrosclerosis with secondary focal segmental glomerulosclerosis (FSGS). Proteinuria could be induced by increased blood flow and pressure due to abnormal blood supply from aberrant renal artery. This is the first report of resolution of proteinuria after TAE of aberrant renal artery in a patient with FSGS.

Relationship between the accuracy of glycemic markers and the chronic kidney disease stage in patients with type 2 diabetes mellitus.

BACKGROUND: It is important to establish glycemic markers which reflect accurate glycemic status in advanced chronic kidney disease (CKD) patients; however, adequate glycemic markers have not been established. We evaluated the accuracy of glycemic markers in non-dialysis CKD patients. PATIENTS AND METHODS: 139 non-dialysis CKD patients with diabetes were enrolled. The patients were divided into three groups as follows: group 1 (G1), patients with an estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m2; group 2 (G2), 30 ≤ eGFR < 60; and group 3 (G3), eGFR < 30. The patients were also classified by serum albumin: patients with serum albumin >= 3.5 g/dL as group S1 (S1) and serum albumin < 3.5 as group S2 (S2). RESULTS: Glycated hemoglobin (A1C) was positively correlated with random PG in G1 and G2; however, no significant correlation was observed in G3. Whereas glycated albumin (GA) was correlated with random PG in S1, there was no significant correlation in S2. To clarify the significance of A1C and GA, the relationships among A1C, GA, and various clinical parameters were examined. GA was correlated with serum albumin and the urinary albumin-creatinine ratio, whereas A1C was significantly correlated with hemoglobin, the dose of recombinant human erythropoietin, and eGFR. CONCLUSION: A1C was affected by eGFR, and GA was influenced by hypoalbuminemia; therefore, it is necessary to choose adequate glycemic markers according to the CKD stage and serum albumin level. GA is a superior glycemic marker in patients with eGFR < 30 mL/min/1.73 m2 and serum albumin >= 3.5 g/dL.

Significance of renal biopsy in patients with presumed diabetic nephropathy.

AIMS/INTRODUCTION: Patients with diabetic nephropathy (DN) typically show varying degrees of proteinuria and renal impairment. Because these clinical signs are frequently observed in other glomerulopathies, renal biopsy is required to make a definitive diagnosis of DN. We carried out the present study to evaluate the significance of renal biopsy for patients who have been presumptively diagnosed with DN. MATERIALS AND METHODS: A total of 55 patients with type 2 diabetes mellitus (DM), and proteinuria, hematuria and/or renal impairment were enrolled in this study. RESULTS: Renal biopsy showed that just 30 patients (54.5%) were histologically diagnosed with DN. Fasting plasma glucose and glycated hemoglobin levels were associated with the presence of DN, whereas baseline renal function showed no statistically significant relationship to DN. The duration of DM was not associated with the presence of DN. Patients with DN had a higher rate of diabetic retinopathy (DR) than those with non-DN (DN 18 patients vs non-DN three patients, P = 0.00029). DN patients with DR showed a more severe renal histology than those without. CONCLUSIONS: These data suggest that, even for patients with long-term DM, renal biopsy should be carried out in patients with presumed DN. Because treatment options differ between DN and primary glomerulopathies, renal biopsy should especially be considered for presumed DN without DR.

Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion.

Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy.

Urinary FSP1 is a biomarker of crescentic GN.

Fibroblast-specific protein 1 (FSP1)-expressing cells accumulate in damaged kidneys, but whether urinary FSP1 could serve as a biomarker of active renal injury is unknown. We measured urinary FSP1 in 147 patients with various types of glomerular disease using ELISA. Patients with crescentic GN, with or without antinuclear cytoplasmic antibody-associated GN, exhibited elevated levels of urinary FSP1. This assay had a sensitivity of 91.7% and a specificity of 90.2% for crescentic GN in this sample of patients. Moreover, we found that urinary FSP1 became undetectable after successful treatment, suggesting the possible use of FSP1 levels to monitor disease activity over time. Urinary FSP1 levels correlated positively with the number of FSP1-positive glomerular cells, predominantly podocytes and cellular crescents, the likely source of urinary FSP1. Even in patients without crescent formation, patients with high levels of urinary FSP1 had large numbers of FSP1-positive podocytes. Taken together, these data suggest the potential use of urinary FSP1 to screen for active and ongoing glomerular damage, such as the formation of cellular crescents.

Clinical significance of fibroblast-specific protein-1 expression on podocytes in patients with focal segmental glomerulosclerosis.

BACKGROUNDS/AIMS: We previously reported that fibroblast-specific protein 1 (FSP1) is a marker of epithelial-mesenchymal transition (EMT) in tubulointerstitial fibrosis. The EMT-like changes observed in podocytes are reportedly associated with podocyte detachment which may cause focal glomerulosclerosis. METHODS: In cross-sectional studies, we analyzed podocyte expression of FSP1 immunohistochemically using renal biopsy specimens from 31 patients with focal segmental glomerulosclerosis (FSGS) and 39 patients with minimal change disease (MCD). We also semiquantitatively analyzed glomerular expression of FSP1 mRNA using laser capture microdissection and real-time PCR. RESULTS: We found that FSP1 was localized to podocytes in both FSGS and MCD patients; however, the number of FSP1(+) podocytes per glomerular profile was significantly higher in patients with FSGS than in those with MCD, and there was a corresponding difference in the levels of FSP1 mRNA. FSP1(+) podocyte counts per glomerular profile in FSGS patients correlated significantly with the prevalence of glomerulosclerosis and the extent of interstitial type-I collagen-positive areas. CONCLUSION: Taken together, these data suggest that podocyte expression of FSP1 could shed light on the potential linkage between EMT-like changes, detachment of podocytes from the glomerular basal membrane and the pathophysiology underlying FSGS.

Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy.

BACKGROUND: Depletion of glomerular podocytes is an important feature of progressive diabetic nephropathy. Although the most plausible explanation for this podocyte depletion is detachment from the glomerular basement membrane after cellular apoptosis, the mechanism is unclear. Fibroblast-specific protein 1 (FSP1; encoded by the S100A4 gene) is a member of the S100 family of calcium-binding proteins and is constitutively expressed in the cytoplasm of tissue fibroblasts or epithelial cells converted into fibroblasts by means of epithelial-mesenchymal transition. STUDY DESIGN: Retrospective cross-sectional analysis. SETTINGS & PARTICIPANTS: 109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy. PREDICTOR: Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy. OUTCOME: FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens. MEASUREMENTS: Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization. RESULTS: 38 of 109 patients (35%) were normoalbuminuric, 16 (15%) had microalbuminuria, 8 (7%) had macroalbuminuria, and 47 (43%) had decreased kidney function. Approximately 95% of podocytes in urine sediment were not apoptotic, and 86% expressed FSP1. The number of FSP1-positive podocytes in urine sediment was significantly larger in patients with macroalbuminuria than in those with normoalbuminuria (P = 0.03). Intraglomerular expression of FSP1 occurred almost exclusively in podocytes from patients with diabetes, and the number of FSP1-positive podocytes was larger in glomeruli showing diffuse mesangiopathy than in those showing focal mesangiopathy (P = 0.01). The number also was larger in glomeruli with nodular lesions than in those without nodular lesions (P < 0.001). FSP1-positive podocytes selectively expressed Snail1 and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition. LIMITATIONS: Nonrepresentative study population. CONCLUSIONS: These results suggest that the appearance of FSP1 in podocytes of patients with diabetes is associated with more severe clinical and pathological findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through epithelial-mesenchymal transition-like phenomena.

Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis.

Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxia-inducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1alpha. HIF-1 regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. To determine the specific role of HIF-1 in renal fibrosis, we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1alpha, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1alpha) histologically and used the anti-HIF-1alpha agent [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1alpha could represent a novel approach to treating renal fibrosis. The area of renal fibrosis was significantly increased in a 5/6 renal ablation model of VHL-/- mice and in all VHL-/- mice at least 60 wk of age. Injection of YC-1 inhibited the progression of renal fibrosis in unilateral ureteral obstruction model mice. In conclusion, HIF-1alpha appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment.

Prediction of corticosteroid responsiveness based on fibroblast-specific protein 1 (FSP1) in patients with IgA nephropathy.

BACKGROUND: Corticosteroids are frequently used to treat patients with active IgA nephropathy (IgAN); however, there have been few reports describing factors that are predictive of the response to corticosteroid treatment. The purpose of this study is to determine the extent to which fibroblast-specific protein 1-positive (FSP1(+)) cells are predictive of corticosteroid responsiveness in patients with IgAN. METHODS: Fifty biopsy-proven IgAN patients who received corticosteroid therapy were enrolled and followed for 7.1 +/- 3.0 years. FSP1(+) cells were identified using an anti-FSP1 antibody. RESULTS: Twelve patients showed progression of renal impairment or no reduction of urinary protein (non-responders) after steroid therapy. In the remaining 38 patients, renal function was stable during follow-up, and their urinary protein declined to <1.0 g/day (responders). Serum creatinine, estimated GFR, severity of mesangial proliferation, percent glomerulosclerosis/total glomeruli, extent of interstitial damage and FSP1(+) cell number were all significantly higher in non-responders than in responders. Cox regression analysis using two covariates with every possible combination of factors indicated that FSP1(+) cell number was the strongest and most significant predictor of corticosteroid responsiveness. When IgAN patients had >32.6 FSP1(+) cells/HPF at diagnosis, they were the more likely to show steroid resistance. CONCLUSION: FSP1(+) cell number can serve as an excellent predictor of corticosteroid responsiveness in patients with IgAN.

ANP is cleared much faster than BNP in patients with congestive heart failure.

OBJECTIVE: To obtain a better understanding of the pharmacokinetics of atrial and brain natriuretic peptides (ANP and BNP, respectively), two peptide mediators used in the treatment of congestive heart failure (CHF). Although both peptides exert their effects by binding to a common receptor (natriuretic peptide receptor A) with about the same affinity, their respective loading and maintenance doses differ. METHODS: Sixteen CHF patients were randomized to be infused for 2 h with alpha-human ANP (0.05 microg/kg per minute) or BNP (0.01 microg/kg per minute). Plasma concentrations of both peptides were measured 0, 2, 5, 15, 30, 60 and 120 min post-infusion. The pharmacokinetic parameters were then calculated using a 1-compartment model. RESULTS: The plasma BNP concentrations in the ANP and BNP groups before infusion were 464.7 +/- 339.8 and 506.8 +/- 332.5 pg/ml, respectively. Following infusion, ANP disappeared from the circulation more rapidly than BNP: their plasma half-lives were 2.4 +/- 0.7 and 12.1 +/- 3.0 min, and their total body clearance volumes were 48.2 +/- 24.1 and 10.1 +/- 2.7 ml/min per kilogram, respectively. CONCLUSION: ANP has a shorter half-life in the plasma of CHF patients than BNP, which suggests that it controls hemodynamics more readily than BNP.

Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN.

BACKGROUND: There is little direct evidence that fibroblasts are involved in the progression of the renal interstitial fibrosis in human glomerulonephritis. With the availability of a new specific marker for fibroblasts, we determined the presence of fibroblasts in kidneys with IgA nephropathy (IgAN) and correlated their numbers with various clinical parameters. In particular, we also prospectively asked if the number of fibroblasts in the renal interstitium correlates with prognosis. METHODS: Cells positive for fibroblast-specific protein 1 (FSP1) were localized in renal biopsy specimens using immunohistochemistry with anti-FSP1 antibody. Clinical features were analyzed by one-way analysis of variance (ANOVA) with the Bonferroni correction. To assess the prognostic impact of the number of FSP1+ fibroblasts on renal survival in 142 patients with normal serum creatinine, the relationship between covariates to renal survival were evaluated univariately using the log-rank test and multivariately using Cox proportional hazards. RESULTS: Fibroblasts identified by their expression of FSP1 accumulate in areas showing severe interstitial fibrosis. Some tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) in fibrotic areas also express FSP1. Numbers of FSP1+ fibroblasts directly correlate with serum creatinine (r = 0.74, P < 0.0001) and inversely correlate with estimated creatinine clearance (r = -0.54, P < 0.0001), and by multivariate analysis, the clinical factors influencing renal survival are urinary protein excretion [> or = 1.0 g/day, relative risk (RR) = 4.20, P= 0.032], hypertension (RR 5.85, P = 0.0027), and > or = 20 FSP1+ fibroblasts per high power field (HPF) (RR 7.39, P = 0.0015). Staining for FSP1+ fibroblasts is largely nonoverlapping with alpha-smooth muscle actin+ (alpha-SMA) cells in the interstitium. CONCLUSION: The target protein FSP1 identifies human fibroblasts and tubular epithelium undergoing EMT, and distinguishes them from the diaspora of alpha-SMA+ vascular smooth muscle cells. FSP1+ fibroblasts are critically related to the progression of IgAN; consequently, staining FSP1 in renal biopsy specimens provides a valuable histologic index of progression.