Tubulointerstitial Score Research Articles

Decreased Expression of Urinary Mammalian Target of Rapamycin mRNA Is Related to Chronic Renal Fibrosis in IgAN.

Background Renal fibrosis is a common outcome of all pathological types of chronic kidney disease (CKD). However, the noninvasive detection of renal fibrosis remains a challenge. Methods We collected urine samples from 154 biopsy-proven IgA nephropathy (IgAN) patients and 61 healthy controls. The expression of mTOR was measured and the correlation with renal function parameter and pathological indicators. The receiver operating characteristic (ROC) curve for the diagnosis of IgAN and renal fibrosis was calculated. Results The urinary mammalian target of rapamycin (mTOR) expression was decreased in IgAN patients. The expression of mTOR was correlated with serum creatinine, blood urea nitrogen, estimated glomerular filtration rate, 24 h proteinuria, and cystatin C. Further, the urinary mTOR expression was significantly decreased in severe renal fibrosis patients compared with mild or moderate renal fibrosis patients. Urinary mTOR expression was correlated with score of tubulointerstitial fibrosis (TIF) and score of glomerular sclerosis. The ROC curve showed that mTOR can diagnose IgAN at a cut-off value of 0.930 with the sensitivity of 90.2% and specificity of 73.8% and renal fibrosis at a cut-off value of 0.301 with the sensitivity of 71.7% and specificity of 64.8%. Conclusion Urinary mTOR mRNA expression was a potential biomarker for diagnosis of IgAN and renal fibrosis in IgAN patients.

Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice.

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.

Predominant global glomerulosclerosis in patients of upper urinary tract urothelial carcinoma with pre-existing renal function impairment is a predictor of poor renal outcomes

BackgroundIncidence of renal dysfunction and risks of progression to end-stage renal disease (ESRD) were reported higher in upper urinary tract urothelial carcinoma (UTUC) than in renal cell carcinoma (RCC) patients after unilateral nephrectomy.MethodsTotally 193 renal cancer patients, including 132 UTUC and 61 RCC, were studied to clarify whether the pathological changes of the kidney remnant removed from nephrectomy and the clinical factors might predict the risk of ESRD. Renal tubulointerstitial (TI) score and global glomerulosclerosis (GGS) rate were examined by one pathologist and two nephrologists independently under same histopathological criteria.ResultsThe glomerular filtration rates at the time of surgery were lower in UTUC than RCC groups (p < 0.001). Average GGS score and average TI rate were higher in UTUC than in RCC groups (p < 0.001; p < 0.001). Competitive risk factor analysis revealed that abnormal GGS rate not related to age, predominant in UTUC with pre-existing renal function impairment, was a histopathological predictor of poor renal outcomes (creatinine doubling or ESRD) within 5 years in UTUC patients.ConclusionPre-existing renal function and pathological change of kidney remnant in both UTUC and RCC have the value for prediction of renal outcomes.

The Value of Serum IgA in the Diagnosis, Clinical and Pathological Evaluation of Patients with IgA Nephropathy Found During Physical Examination in China.

The goal was to study the role of serum IgA in patients with IgA nephropathy (IgAN) found during physical examination, and to explore its value in diagnosis, assessment of pathological injury, and clinical prediction of IgAN. The study included 457 patients who were hospitalized between January 2010 and June 2018 due to physical abnormalities and diagnosed with kidney disease via renal biopsy. Renal histopathology was quantified according to Katafuchi semi-quantitative standards, while the IgAN patients were also scored according to Lee's grading system. The average age of the 457 patients was 39.62 ± 13.52 years when abnormalities were found during physical examination. IgAN (202 cases, 46.12%) was the most common type of primary glomerulonephritis in the 457 patients. Of the IgAN patients, 75.25% (152 cases) were under 45 years old at the time of abnormal physical examination and IgAN patients were significantly younger than non-IgAN patients. There was a significant difference in the gender ratio between IgAN patients and non-IgAN patients (χ2 = 4.24, p = 0.039). In IgAN patients, the proportion of male patients, serum creatinine (SCr), the glomerular lesion and tubulointerstitial scores, and serum IgA were statistically higher than in non-IgAN patients with other types of primary glomerulonephritis; however, MDRD-GFR was lower. The ROC curve of serum IgA in the diagnosis of IgAN showed the AUC was 0.602. One hundred forty-seven cases (72.77%) were Lee's III - V grade. The proportion of patients who were at Lee's III - V grades in the normal serum IgA group (184 cases) was higher than that of the elevated serum IgA group (18 cases). There were no significant differences in gross hematuria, proteinuria, MDRD-GFR, SCr, and hypertension between the two groups. Serum IgA may be of little value in the diagnosis of patients with IgA nephropathy detected via physical examination. The level of serum IgA may have predictive value in evaluating Lee's pathological damage in IgAN patients.

Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease.

Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes II-III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl-β-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-α (TNF-α) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-α levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-α expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD.

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy.

ABSTRACTAimTrefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN).MethodsWe investigated the renal mRNA expression of TFF3 by real‐time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively.ResultsThe renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients.ConclusionRenal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients.

Role of Sirolimus in renal tubular apoptosis in response to unilateral ureteral obstruction.

Renal tubule cell apoptosis plays a pivotal role in the progression of chronic renal diseases. The previous study indicates that Sirolimus is effective on unilateral ureteral obstruction (UUO)-induced renal fibrosis. However, the role of Sirolimus in renal tubular apoptosis induced by UUO has not yet been addressed. The aim of this study was to determine the role of Sirolimus in renal tubular apoptosis induced by UUO. Male Sprague-Dawley rats were divided into three groups, sham-operated rats, and after which unilateral ureteral obstruction (UUO) was performed: non-treated and sirolimus-treated (1mg/kg). After 4, 7 and 14 d, animals were sacrificed and blood, kidney tissue samples were collected for analyses. Histologic changes and interstitial collagen were determined microscopically following HE and Masson's trichrome staining. The expression of PCNA was investigated using immunohistochemistry and the expression of Bcl-2, Bax, caspase-9, and caspase-3 were investigated using Western blot in each group. Tubular apoptotic cell deaths were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Sirolimus administration resulted in a significant reduction in tubulointerstitial fibrosis scores. After UUO, there was an increase in tubular and interstitial apoptosis in untreated controls as compared to Sirolimus treatment rats (P<0.05). In addition, the expression of PCNA, Bcl-2, Bax, caspase-9, and caspase-3 in obstructed kidney was characterized by immunohistochemistry and Western blot analyses demonstrating that sirolimus treatment significantly reduced PCNA, Bax, caspase-9 and cleaved caspase-3 expression compared to those observed in controls (P<0.05), whereas, Bcl-2 in the obstructed kidney were decreased in untreated controls compared to Sirolimus treatment rats subjected to the same time course of obstruction (P<0.05). We demonstrated a marked renoprotective effect of sirolimus by inhibition of UUO-induced renal tubular apoptosis in vivo.

Inflammatory Response Modulation through a PPARγ Agonist during Surgically Induced Visceral Ischemia in an Animal Model

Ischemia/reperfusion (I/R) injury represents one of the most severe complications in vascular surgery where cross-clamping of the aorta and subsequent visceral ischemia are a recurrent issue. The literature describes a family of nuclear receptors, that is, peroxisome proliferator-activated receptors (PPARs), in particular PPARγ isoform, which are important modulators of vascular inflammation resulting from I/R injury. The aim of our study is to evaluate how PPARγ agonist administration could reduce local and systemic inflammatory response after I/R injury during aortic supraceliac clamping in animal model. Our model includes 16 rats divided as follows: 8 rats in the placebo control group (PlacG) were operated on without having been administered of any drugs during the preoperative period, whereas the 8 rats in the pioglitazone group (PioG) were pretreated with pioglitazone. Renal and visceral ischemias were induced in the rats by supraceliac aortic clamping. Rats were sacrificed after surgery, and then, we collected blood samples to measure serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) and one of the kidneys and a segment of the liver to perform histological analysis. Considering both cytokines in the PioG, there has been a negative trend in serum concentrations, whereas in the PlacG, we observed an increasing trend. The high standard deviation observed in our study is mainly due to the small population of the cohort. Histologic examination of the kidney showed more severe damage in the placebo group as compared to the PioG with more evident differences in tubular and tubulointerstitial scores. Our observations show that administering pioglitazone can partially reduce secondary inflammatory response in the ischemic insult especially in endothelial and perivascular tissues.

Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice.

Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Faslpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Faslpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Faslpr mice also showed elevated serum CatK levels. CatK deficiency in Faslpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Faslpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Faslpr mouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+ Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Faslpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.

Urinary and tissue monocyte chemoattractant protein1 (MCP1) in lupus nephritis patients

Aim of the workTo assess the role of urinary and tissue monocyte chemoattractant protein-1 (MCP-1) in active lupus nephritis (LN) and to correlate the levels with disease activity and renal status. Patients and methodsUrinary and tissue MCP-1 were determined in 42 systemic lupus erythematosus (SLE) patients with LN. 20 matched controls were considered. SLE disease activity index (SLEDAI) was recorded in all patients. Urinary and renal tissue MCP-1 was evaluated. Renal biopsy was performed in active LN patients for histopathological classification and correlation. Results22 active LN patients (22.8±4.7years old) and 20 inactive (24.6±4.3years old) were studied. They were 39 female and 3 males (F:M 13:1). The urinary MCP-1 was significantly higher in active LN patients (1072.8±658.4pg/mg creatinine) compared to the inactive group (151.3±103.5pg/mg creatinine) and both were significantly higher than the level in the controls (19±17.8pg/mg creatinine) (p<0.001). A significant correlation was present in the active LN patients between urinary MCP-1 level and proteinuria, anti-dsDNA, renal SLEDAI and biopsy activity index and negatively with C3 and C4. There was a significant correlation of the glomerular MCP-1 renal tissue expression score with the renal SLEDAI, anti-dsDNA, biopsy activity index and urinary MCP-1 and negatively with C3. Tubulointerstitial MCP-1 score significantly correlated with urinary MCP-1. Urinary, glomerular and tubular MCP-1 showed a sensitivity of 97%, 64% and 4% and specificity of 100%, 95% and 20% respectively in detecting LN. ConclusionMCP-1 could be a valuable marker for LN and disease activity.

Vitamin D deficiency may predict a poorer outcome of IgA nephropathy.

BackgroundExperimental studies showed that 25-hydroxy-vitamin D [25(OH)D] deficiency (defined as 25-hydroxy-vitamin D < 15 ng/ml) has been associated with CKD progression. Patients with IgA nephropathy have an exceptionally high rate of severe 25(OH)D deficiency; however, it is not known whether this deficiency is a risk factor for progression of IgA nephropathy. We conducted this study to investigate the relationship between the plasma level of 25(OH)D and certain clinical parameters and renal histologic lesions in the patients with IgA nephropathy, and to evaluate whether the 25(OH)D level could be a good prognostic marker for IgA nephropathy progression.MethodsA total of 105 patients with biopsy-proven IgA nephropathy were enrolled between 2012 and 2015. The circulating concentration of 25(OH)D was determined using serum samples collected at the time of biopsy. The primary clinical endpoint was the decline of estimated glomerular filtration rate (eGFR; a 30 % or more decline compared to the baseline).ResultsMean eGFR decreased and proteinuria worsened proportionally as circulating 25(OH)D decreased (P < 0.05). The 25(OH)D deficiency was correlated with a higher tubulointerstitial score by the Oxford classification (P = 0.008). The risk for reaching the primary endpoint was significantly higher in the patients with a 25(OH)D deficiency compared to those with a higher level of 25(OH)D (P = 0.001). As evaluated using the Cox proportional hazards model, 25(OH)D deficiency was found to be an independent risk factor for renal progression [HR 5.99, 95 % confidence intervals (CIs) 1.59–22.54, P = 0.008].ConclusionA 25(OH)D deficiency at baseline is significantly correlated with poorer clinical outcomes and more sever renal pathological features, and low levels of 25(OH)D at baseline were strongly associated with increased risk of renal progression in IgAN.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0378-4) contains supplementary material, which is available to authorized users.

The significance of tubulointerstitial lesions in childhood Henoch-Schönlein nephritis.

Little information is currently available on the development of tubulointerstitial lesions in children with Henoch-Schönlein nephritis (HSN). To identify the impact of the development of tubulointerstitial changes in HSN, we retrospectively analyzed renal biopsies obtained from children with HSN. Twenty-eight children with HSN from whom serial renal biopsies had been obtained before and after immunosuppressive therapy were enrolled in the study. The patients were divided into two groups according to the observed change in tubulointerstitial lesion development: group I (n = 15), with stable or improved tubulointerstitial lesions, and group II (n = 13), with worsened tubulointerstitial lesions. Group II patients had longer duration of proteinuria than group I patients (3.7 ± 3.7years vs. 1.7 ± 1.7years, p = 0.052). The change in serum albumin level was negatively correlated with the change in tubulointerstitial scores before and after treatment (γ = -0.444, p = 0.018). Group II patients showed a significant decrease in immunoglobulin G (IgG) and IgA deposits after treatment (p = 0.039 and 0.003, respectively), while group II patients did not (p = 0.458 and 0.506, respectively). Although the International Study of Kidney Disease in Children classification of HSN does not include tubulointerstitial lesions, they can progress during treatment and could have significant clinical implications in association with the duration of proteinuria.

Expression and significance of microRNA-21 in acute kidney injury renal of mice

Objective To investigate the expression and significance of microRNA-21(miR-21) in acute kidney injury mice model at the different time points following ischemic/reperfusion. Methods C57BL/6J mice were divided into 3 major groups: the control group (C group), sham operation group(S group) and ischemia-reperfusion group (IR group). Later 2 groups were divided into 9 sub-groups respectively according to the time following reperfusion.Automatic biochemical analyzer detected serum creatinine (Scr), blood urea nitrogen (BUN) level.HE staining detected renal pathological damage.Renal tubulointerstitial pathological score accessed pathological damage.Real time-PCR tested the expression of miR-21 and mitogen-activated protein kinase kinase 3(MKK3) mRNA in renal respectively.Immunohistochemistry staining tested expression of MKK3. Results IR group's Scr, BUN levels gradually increased following reperfusion, 24 h reached its peak, then gradually declined.The Scr, BUN level had statistically significant difference between IR group and S group at the same time subgroup from 3 h to 168 h following reperfusion(all P<0.01). The change of kidney damage and pathological changes of interstitial and tubular injury score consensus with renal function.miR-21 increased gradually in renal ischemia after reperfusion, 24 h peaked and then stabilized at this high level.miR-21 was positively correlated with pathological tubulointerstitial injury from 0 h to 168 h after reperfusion (r=0.969, P<0.05). IR group's MKK3 mRNA and protein expression rose sharply following ischemia/reperfusion, 24 h peaked, and then gradually decreased.From 3 h to 168 h, the expression of MKK3 mRNA and proteins had significant difference at each same time points subgroups between IR group and S group(all P<0.01). Conclusions miR-21 increases gradually in renal ischemia after reperfusion, 24 h peaked and then stabilized at this high level.miR-21 is positively correlated with pathological tubulointerstitial injury, which may be associated with the negative regulated relationship between miR-21 and MKK3. Key words: microRNA-21; Ischemia-reperfusion injury; Acute kidney injury; Mitogen-activated protein kinase kinase 3

Tacrolimus restores podocyte injury and stabilizes the expression of Cabin1 in 5/6 nephrectomized rats

Podocyte injury is a vital factor, which induces massive proteinuria. Studies have shown that tacrolimus (TAC) protected podocyte via stabilizing cytoskeleton. Our latest study indicates that calcineurin binding protein 1 (Cabin1) undergoes nuclear translocation during podocytes injury. Whether TAC targets on Cabin1 during podocyte injury is still not clear. This study establishes non-immunological proteinuric model. To observe the effect of the treatment of TAC on Cabin1 expression in 5/6 nephrectomized rats. Sprague–Dawley rats were injected with TAC (0.2 mg/kg/day) for 4–8 weeks after 5/6 nephrectomy. Then, rats were sacrificed in the eighth week after operation, renal tissues were processed for morphological studies under light and electrical microscope. Cabin1 expression and distribution were detected by western blot and indirect immunofluorescence staining. In 5/6 nephrectomized rats, urinary protein excretion reached 90.2 ± 30.1 mg/24 h, glomerular sclerosis index and tubulointerstitial fibrosis score were significantly increased, and widespread of podocyte foot processes fusion was found. Moreover, Cabin1 protein expression was markedly increased, and its distribution became much more obviously in podocytes nuclei. In TAC treated rats, urinary protein excretion significantly decreased (44.9 ± 22.5 mg/24 h), glomerular sclerosis and tubulointerstitial fibrosis were alleviated, and podocyte foot processes fusion was inhibited. Furthermore, TAC alleviated the increased protein expression and abnormal distribution of Cabin1. In conclusion, TAC restores podocyte injury and stabilizes the expression of Cabin1. Cabin1 may become a new target to demonstrate the mechanism of TAC in podocyte injury.

Atorvastatin improves pathological changes in the aged kidney by upregulating peroxisome proliferator-activated receptor expression and reducing matrix metalloproteinase-9 and transforming growth factor-β1 levels

ObjectiveTo investigate the effects of atorvastatin (AVT) on renal function and renal pathological changes in the aged rat and explore their possible mechanisms. MethodsTwenty-month-old, normal female Wistar rats were divided into three groups: group A (n=8) was fed high-dose AVT (10mg/kg/d); group B (n=8) was fed low-dose AVT (1mg/kg/d); and group C (controls, n=8) received the same volume of normal saline; 3-month-old, normal female Wistar rats served as young normal controls (n=8). All rats were sacrificed following a 4-month treatment period. Serum creatinine and blood lipid levels were measured. The glomerular sclerosis index and tubulointerstitial lesions were determined using renal periodic acid–Schiff-stained paraffin sections. The mRNA and protein expressions of matrix metalloproteinases (MMP)-9 and -2, tissue inhibitors of metalloproteinase (TIMP)-1 and -2, transforming growth factor-β1 (TGF-β1), and peroxisome proliferator-activated receptors (PPARs) were examined using reverse transcription polymerase chain reactions and Western blots, respectively. ResultsSerum lipid (including serum cholesterol and serum triglycerides) levels in aged rats were significantly higher than those in young rats (p<0.05). Compared to the aged control group, high-dose AVT was associated with significantly lower serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels in aged rats (p<0.05); low-dose AVT was associated only with lower serum LDL-C levels (p<0.05). Renal morphological changes in aged rats included focal glomerulosclerosis, infiltration of inflammatory cells, and arteriole sclerosis. Improved renal pathology was observed in aged, AVT-treated rats, and included a decreased glomerular sclerosis index and tubulointerstitial lesion score, especially in those receiving high-dose AVT. Additionally, renal artery wall thickening, luminal narrowing, and arteriolosclerosis were significantly less severe in aged rats receiving high-dose AVT. Upregulated expression of MMP-9 and TGF-β1 was observed in the renal tissue of aged rats. AVT treatment was associated with a reversal of these phenomena and upregulated expression of TIMP-1, PPARα, PPARβ, and PPARγ in aged rats. ConclusionAVT improved the renal pathology of aged rats. These effects may have been induced by the lowering of blood lipids, maintaining the MMP/TIMP balance, and downregulating the expression of TGF-β1. AVT may reduce the levels of MMP-9 and TGF-β in aged rats by upregulating the expression of PPARs.

Serum level of proximal renal tubular epithelial cell-binding immunoglobulin G in patients with lupus nephritis.

In vitro data showed that immunoglobulin G (IgG) from lupus nephritis (LN) patients could bind to proximal renal tubular epithelial cells (PTEC), but the clinical relevance of such binding remained unclear. Binding of IgG and subclasses to PTEC was measured by cellular ELISA (expressed as OD index) in 189 serial serum samples from 23 Class III/IV ± V LN patients who had repeated renal flares (48 during renal flares, 141 during low level disease activity (LLDA)), and compared with 64 patients with non-lupus glomerular diseases (NLGD) and 23 healthy individuals. Total IgG PTEC-binding index was 0.34 ± 0.16, 0.29 ± 0.16, 0.62 ± 0.27 and 0.83 ± 0.38 in healthy controls, NLGD, LN patients during LLDA, and LN patients during nephritic flare, respectively (p < 0.001, LLDA vs. renal flare; p < 0.001, healthy controls or NLGD vs. LN during LLDA or renal flare). PTEC-binding index for IgG1 was 0.09 ± 0.05, 0.16 ± 0.12, 0.44 ± 0.34 and 0.71 ± 0.46 for the corresponding groups (p < 0.001, LLDA vs. renal flare; p < 0.001, healthy controls or NLGD vs. LN during LLDA or renal flare). Sixteen of 48 episodes (33.3%) of nephritic flare showed persistent PTEC-binding IgG seropositivity for more than 9.4 ± 3.1 months, despite clinical response to immunosuppressive treatment. Total IgG and IgG1 PTEC-binding correlated with anti-dsDNA level (r = 0.34 and 0.52, respectively, p < 0.001 for both), and inversely with C3 level (r = -0.26 and -0.50, respectively, p = 0.002 and<0.001). Sensitivity/specificity of PTEC-binding index in detecting renal flares was 45.8%/80.1% for total IgG (ROC AUC 0.630, p = 0.007) and 87.5%/35.5% for IgG1 (ROC AUC 0.615, p = 0.018). IgG1 PTEC-binding index correlated with tubulo-interstitial inflammation score in renal biopsy from corresponding patients. Our data suggested that total IgG and IgG1 PTEC-binding index in serum of LN patients correlate with serological activity, and in combination could predict renal flares. The correlation between IgG1 PTEC-binding and tubulo-interstitial inflammation suggests potential pathogenetic significance.

Noninvasive evaluation of renal oxygenation in primary nephrotic syndrome with blood oxygen level dependent magnetic resonance imaging: Initial experience

To use blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) to evaluate renal oxygenation in patients with primary nephrotic syndrome (PNS), and test the hypothesis that renal tissue oxygenation correlates with renal function, tubulointerstitial alterations and treatment response. Patients with untreated first-onset PNS and healthy control subjects underwent BOLD MRI. Blood and urine samples were obtained on the day of MRI, and patients underwent renal biopsy the day after MRI. Renal tubulointerstitial damage scores (TIDS) were determined using Katafuchi criteria. All patients received corticosteroids within 7 days after MRI and were followed up for 12 months. Medullary R2* values were significantly lower in patients with PNS (n = 20) than controls (n = 18). Medullary R2* values were negatively correlated with estimated glomerular filtration rates and positively correlated with TIDS in patients with PNS. There were no significant differences in medullary or cortical R2* values when patients were classified according to treatment response. The medullary oxygen concentration was higher in patients with PNS than in control subjects. BOLD MRI was a useful noninvasive method for the evaluation of renal function and tubulointerstitial impairment.

Effects of oral carbonic adsorbent (AST-120) on kidney of early-stage chronic kidney disease rats

Aim: to investigate the therapeutic effects of oral carbonic adsorbent on rats with early-stage renal failure. Methods: The early-stage renal failure model was established with three-fourth subtotal nephrectomy Wistar rats. Four weeks after the subtotal nephrectomy, the rats were randomly divided into four groups: (1) adsorbent diet (AD) rats; (2) low protein diet (LPD) group; (3) low protein and AD rats; and (4) normal diet rats as control (ctrl) group. Sham operation group is set as well. The therapeutic effects of adsorbent were examined after 15 weeks treatment. Results: The level of 24 hours urinary protein excretion, serum creatinine (Scr), index of glomerulosclerosis (GSI) and tubulointerstitial fibrosis score (TIFS) of rats with adsorbent or LPD treatment are significantly lower than ctrl group rats. The combination of adsorbent and LPD lowered level of 24 hours urinary protein excretion, Scr, index of GSI and TIFS compared with LPD or adsorbent treatment alone. Conclusion: Both AST-120 and LPD treatment lowered the Scr and blood urea nitrogen level as well as ameliorated the proteinuria and glomerular and tubulointerstitial damage of rats with early stage renal failure. The combined treatment of oral carbonic adsorbent and LPD showed greater therapeutic effects.

Clinicopathological role of kidney injury molecule-1 in immunoglobulin A nephropathy

BackgroundUrinary kidney injury molecule-1 (KIM-1) is an early and sensitive biomarker of acute kidney injury, but it is unclear if it is a biomarker of chronic glomerulonephritis. We evaluated whether urinary KIM-1 levels in patients with immunoglobulin A (IgA) nephropathy can be a marker to reflect clinicopathological severity and predict the prognosis. MethodsWe measured urinary KIM-1 levels in 40 patients (15 males; mean age 36.6±12.9 years) with IgA nephropathy and 10 healthy people (5 males; mean age 37.3±9.6 years) as controls. The correlation of urinary KIM-1 levels with patients’ clinical parameters, histological grades, and follow-up data were analyzed using the modified H. S. Lee grading system and tubulointerstitial change scores. ResultsUrinary KIM-1 levels were higher in patients with IgA nephropathy than healthy controls (P=0.001). Univariate and multivariate regression analyses showed that urinary KIM-1 levels had a direct correlation with H. S. Lee grade and tubulointerstitial inflammation (P=0.004 and P=0.011, respectively). ConclusionIn patients with IgA nephropathy, urinary KIM-1 has a significant correlation with histopathologic severity.

Impact of bone-marrow-derived mesenchymal stem cells on adriamycin-induced chronic nephropathy.

To study the effects of bone-marrow-derived mesenchymal stem cells (BM-MSCs) on adriamycin (ADR)-induced chronic nephropathy in rats. 60 male Sprague-Dawley rats were distributed among 3 groups (20 rats each): (i) the negative control group, which was normal rats that received saline (vehicle); (ii) the positive control (ADR) group, which was rats that received 2 intravenous injections of ADR into the penile vein at 14 day intervals without treatment, and (iii) the MSC group, which were rats treated as for the ADR group that were also given 2 intravenous injections of MSCs (5 days after each ADR injection). ADR caused a significant reduction in animal body mass, survival rate, hemoglobin (Hb) content, serum albumin, and renal GSH, and significantly increased serum levels of triglycerides, cholesterol, urinary protein excretion and kidney injury molecule-1 (KIM-1), renal MDA, as well as caspase-3 expression and glomerular and tubulointerstitial damage compared with the negative control group. MSC treatment failed to improve animal survival rate, body mass, Hb level, proteinuria, or hypoalbuminemia; however, it mildly improved the serum BUN, hyperlipidemia, caspase-3 expression, urinary levels of KIM-1, renal oxidative stress markers, and glomerular and tubulointerstitial damage score. administration of BM-MSCs during induction of ADR nephropathy provides partial protection, which could be due to improvements in the levels of of endogenous antioxidants, reduction of apoptosis, and maintenance of the integrity of the glomerular membrane.