Clinical Significances of Anti-Collagen Type I and Type III Antibodies in Antibody-Mediated Rejection.

It is important to determine the clinical significance of non-human leukocyte antigen (HLA) antibodies and their association with antibody-mediated rejection (ABMR) of kidney allografts. We collected post-transplant sera from 68 ABMR patients, 67 T-cell mediated rejection (TCMR) patients, and 83 control subjects without rejection, and determined the titers of 39 non-HLA antibodies including antibodies for angiotensin II receptor type I and MICA. We compared all these non-HLA antibody titers among the study groups. Then, we investigated their association with the risk of death-censored graft failure in ABMR cases. Among the antibodies evaluated, anti-collagen type I (p = 0.001) and type III (p < 0.001) antibody titers were significantly higher in ABMR cases than in both TCMR cases and no-rejection controls. Both anti-collagen type I [per 1 standard deviation (SD), adjusted odds ratio (OR), 11.72 (2.73-76.30)] and type III [per 1 SD, adjusted OR, 6.22 (1.91-31.75)] antibodies were significantly associated with the presence of ABMR. Among ABMR cases, a higher level of anti-collagen type I [per 1 SD, adjusted hazard ratio (HR), 1.90 (1.32-2.75)] or type III per 1 SD, [adjusted HR, 1.57 (1.15-2.16)] antibody was associated with a higher risk of death-censored graft failure. In conclusion, post-transplant anti-collagen type I and type III antibodies may be novel non-HLA antibodies related to ABMR of kidney allografts.

Klotho ameliorates diabetic nephropathy via LKB1-AMPK-PGC1α-mediated renal mitochondrial protection.

Diabetic nephropathy (DN) is associated with renal mitochondrial injury and decreased renal klotho expression. Klotho is known as an aging suppressor, and mitochondrial dysfunction is the hallmark of aging. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a master regulator of mitochondrial biogenesis, and adenosine monophosphate-activated protein kinase (AMPK) is known as a guardian of mitochondria. Here, we report that recombinant soluble klotho protein (rKL) protects against DN in db/db mice via PGC1α-AMPK-mediated mitochondrial recovery in the kidney. We injected rKL into db/db and db/m mice for 8 weeks and collected the serum and kidney tissue. We treated murine renal tubular cells with rKL in vitro, with and without exposure to 30 mM high glucose (HG). rKL treatment ameliorated major disorders from diabetes, such as obesity, hyperglycemia, and intrarenal reactive oxygen species (ROS) generation, in db/db mice. rKL also diminished albuminuria, recovered renal proximal tubular mitochondria, increased renal p-AMPK and PGC1α, and down-regulated mTOR/TGF-ß in db/db mice. In S1 mouse proximal tubular cells, rKL treatment ameliorated HG-mediated cellular and mitochondrial damage and enhanced oxidative phosphorylation, with an increase in PGC1α-AMPK-induced mitochondrial recovery. Our data suggest that klotho exerts a mitochondrial protective effect in diabetic kidney disease by inducing AMPK-PGC1α expression.

Hemorrhagic Transformation After Large Cerebral Infarction in Rats Pretreated With Dabigatran or Warfarin.

BACKGROUND AND PURPOSE: It is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is less frequent in dabigatran users than warfarin users. We compared the occurrence of HT after large cerebral infarction among rats pretreated with dabigatran, warfarin, or placebo. METHODS: This was a triple-blind, randomized, and placebo-controlled experiment. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or saline for 7 days, Wistar rats were subjected to transient middle cerebral artery occlusion. As the primary outcome, HT was determined by gradient-recalled echo imaging. For the secondary outcome, intracranial hemorrhage was assessed via gradient-recalled echo imaging in surviving rats and via autopsy for dead rats. RESULTS: Of 62 rats, there were 33 deaths (53.2%, 17 technical reasons). Of the intention-to-treat population, 33 rats underwent brain imaging. HT was less frequent in the dabigatran group than the warfarin group (placebo 2/14 [14%], dabigatran 0/10 [0%], and warfarin 9/9 [100%]; dabigatran versus warfarin; P<0.001). In all 62 rats, compared with the placebo (2/14 [14.3%]), the incidence of intracranial hemorrhage was significantly higher in the warfarin group (19/29 [65.5%]; P=0.003), but not in the dabigatran group (6/19 [31.6%]; P=0.420). Mortality was significantly higher in the warfarin group than the dabigatran group (79.3% versus 47.4%; P=0.022), but not related to the hemorrhage frequency. CONCLUSIONS: The risk of HT after a large cerebral infarction was significantly increased in rats pretreated with warfarin than those with dabigatran. However, the results here may not have an exact clinical translation.

Time-Dependent Thrombus Resolution After Tissue-Type Plasminogen Activator in Patients With Stroke and Mice.

BACKGROUND AND PURPOSE: We investigated the relationship between the degree of thrombus resolution and the time from stroke onset or thrombus formation to intravenous tissue-type plasminogen activator (tPA) treatment. METHODS: In patients with stroke, we measured thrombus volume on thin-section noncontrast brain computed tomographic scans taken at baseline and 1 hour after tPA administration. We determined the association between the time from symptom onset to tPA treatment and the degree of thrombus resolution. In a C57/BL6 mouse model of FeCl3-induced carotid artery thrombosis, we investigated the effect of tPA administered at different time intervals after thrombus formation, using Doppler-based blood flow measurement. RESULTS: Of 249 patients enrolled, 171 showed thrombus on baseline computed tomography. Thrombus was resolved by ≥50% in 43 patients (25.1%, good volume reduction) and by <50% in 94 patients (55.0%, moderate volume reduction) 1 hour after tPA treatment. In 34 patients (19.9%, nonvolume reduction; either no change or thrombus volume increased), overall thrombus volume increased. The probability of thrombus resolution decreased as the time interval from symptom onset to treatment increased. On multivariate analysis, good volume reduction was independently related with shorter time intervals from symptom onset to tPA treatment (odds ratio, 0.986 per minute saved; 95% confidence interval, 0.974-0.999). In the mouse model, as the interval between thrombus formation and tPA treatment increased, the initiation of recanalization was delayed (P=0.006) and the frequency of final recanalization decreased (P for trends=0.006). CONCLUSIONS: Early administration of tPA after stroke onset is associated with better thrombus resolution.

Unveiling the role of transgelin as a prognostic and therapeutic target in kidney fibrosis via a proteomic approach.

Chronic kidney disease (CKD) progression involves tubulointerstitial fibrosis, a process characterized by excessive extracellular matrix accumulation. To identify potential biomarkers for kidney fibrosis, we performed mass spectrometry-based proteomic profiling of human kidney tubular epithelial cells and kidney tissue from a 5/6 nephrectomy rat model. Multidisciplinary analysis across kidney fibrosis models revealed 351 differentially expressed proteins associated with kidney fibrosis, and they were enriched in processes related to the extracellular matrix, kidney aging, and mitochondrial functions. Network analysis of the selected proteins revealed five crucial proteins, of which transgelin emerged as a candidate protein that interacts with known fibrosis-related proteins. Concordantly, the gene expression of transgelin in the kidney tissue from the 5/6 nephrectomy model was elevated. Transgelin expression in kidney tissue gradually increased from intermediate to advanced fibrosis stages in 5/6 Nx rats and mice with unilateral ureteral obstruction. Subsequent validation in kidney tissue and urine samples from patients with CKD confirmed the upregulation of transgelin, particularly under advanced disease stages. Moreover, we investigated whether blocking TAGLN ameliorated kidney fibrosis and reduced reactive oxygen species levels in cellular models. In conclusion, our proteomic approach identified TAGLN as a potential noninvasive biomarker and therapeutic target for CKD-associated kidney fibrosis, suggesting its role in modulating mitochondrial dysfunction and oxidative stress responses.

Association of plasma osteoprotegerin levels with stroke severity and functional outcome in acute ischaemic stroke patients.

Osteoprotegerin (OPG) is known to regulate processes involved in vascular injury and inflammation. We investigated the relationship between plasma OPG levels and stroke subtype, stroke severity at admission and functional outcome at 3 months in 172 patients with acute ischaemic stroke. Patients with large artery atherosclerosis and those with multiple causes had higher plasma OPG levels than patients with lacune. Increased plasma OPG levels were independently associated with more severe stroke and poor functional outcome. These results suggest pleiotropic roles of OPG in mediating atherosclerosis and ischaemic brain injury. OPG is a potential biomarker for predicting neurologic outcome in stroke.

Chemokine (C-C Motif) Ligand 8 and Tubulo-Interstitial Injury in Chronic Kidney Disease.

Kidney fibrosis has been accepted to be a common pathological outcome of chronic kidney disease (CKD). We aimed to examine serum levels and tissue expression of chemokine (C-C motif) ligand 8 (CCL8) in patients with CKD and to investigate their association with kidney fibrosis in CKD model. Serum levels and tissue expression of CCL8 significantly increased with advancing CKD stage, proteinuria level, and pathologic deterioration. In Western blot analysis of primary cultured human tubular epithelial cells after induction of fibrosis with rTGF-ß, CCL8 was upregulated by rTGF-ß treatment and the simultaneous treatment with anti-CCL8 mAb mitigated the rTGF-ß-induced an increase in fibronectin and a decrease E-cadherin and BCL-2 protein levels. The antiapoptotic effect of the anti-CCL8 mAb was also demonstrated by Annexin V/propidium iodide staining assay. In qRT-PCR analysis, mRNA expression levels of the markers for fibrosis and apoptosis showed similar expression patterns to those observed by western blotting. The immunohistochemical analysis revealed CCL8 and fibrosis- and apoptosis-related markers significantly increased in the unilateral ureteral obstruction model, which agrees with our in vitro findings. In conclusion, CCL8 pathway is associated with increased risk of kidney fibrosis and that CCL8 blockade can ameliorate kidney fibrosis and apoptosis.

Inhibiting Transglutaminase 2 Mediates Kidney Fibrosis via Anti-Apoptosis.

Transglutaminase 2 (TG2) is a calcium-dependent transamidating acyltransferase enzyme of the protein-glutamine γ-glutamyltransferase family implicated in kidney injury. In this study, we identified associations between TG2 and chronic kidney disease (CKD) identified by visualizing TG2 in kidney biopsy samples derived from CKD patients using immunohistochemistry and measuring the plasma TG2 concentrations. Our study revealed a connection between TG2 and the pathological markers of kidney disease. We showed high plasma TG2 levels in samples from patients with advanced CKD. In addition, we observed an increase in TG2 expression in tissues concomitant with advanced CKD in human samples. Moreover, we investigated the effect of TG2 inhibition on kidney injury using cystamine, a well-known competitive inhibitor of TG2. TG2 inhibition reduced apoptosis and accumulation of extracellular molecules (ECM) such as fibronectin and pro-inflammatory cytokine IL-8. Collectively, the increased expression of TG2 that was observed in advanced CKD, hence inhibiting TG2 activity, could protect kidney cells from ECM molecule accumulation, apoptosis, and inflammatory responses, thereby preventing kidney fibrosis.

Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy.

Kruppel-like factor 2 (KLF2) regulates endothelial cell metabolism; endothelial dysfunction is associated with hypertension and is a predictor of atherosclerosis development and cardiovascular events. Here, we investigated the role of KLF2 in hypertensive nephropathy by regulating KLF2 expression in human primary glomerular endothelial cells (hPGECs) and evaluating this expression in the kidney tissues of a 5/6 nephrectomy mouse model as well as patients with hypertension. Hypertension-mimicking devices and KLF2 siRNA were used to downregulate KLF2 expression, while the expression of KLF2 was upregulated by administering simvastatin. After 4 mmHg of pressure was applied on hPGECs for 48 h, KLF2 mRNA expression decreased, while alpha-smooth muscle actin (αSMA) mRNA expression increased. Apoptosis and fibrosis rates were increased under pressure, and these phenomena were aggravated following KLF2 knockdown, but were alleviated after simvastatin treatment; additionally, these changes were observed in angiotensin II, angiotensin type-1 receptor (AT1R) mRNA, and interleukin-18 (IL-18), but not in angiotensin type-2 receptor mRNA. Reduced expression of KLF2 in glomerular endothelial cells due to hypertension was found in both 5/6 nephrectomy mice and patients with hypertensive nephropathy. Thus, our study demonstrates that the pressure-induced apoptosis and fibrosis of glomerular endothelial cells result from angiotensin II, AT1R activation, and KLF2 inhibition, and are associated with IL-18.

Dabigatran reduces endothelial permeability through inhibition of thrombin-induced cytoskeleton reorganization.

Dabigatran etexilate (DE), a new oral anti-coagulant, is a direct thrombin inhibitor. Clinical trials showed the favorable benefit-to-risk profile of DE compared to warfarin for the prevention of ischemic stroke in patients with atrial fibrillation. Remarkably, patients treated with dabigatran showed reduced rates of intracerebral hemorrhage compared to warfarin. As the breakdown of endothelial barrier integrity is associated with hemorrhagic events and as thrombin increases endothelial permeability, we hypothesized that dabigatran preserves the endothelial barrier by inhibiting thrombin-induced permeability. We assessed leakage of fluorescein isothiocyanate (FITC)-dextran through the endothelial monolayer and measured trans-endothelial electrical resistance of the endothelial monolayer after treatment of thrombin or thrombin pre-incubated with dabigatran. Thrombin increased the permeability of endothelial cells. Dabigatran effectively blocked the ability of thrombin to increase permeability. Dabigatran inhibited the formation of actin stress fibers induced by thrombin and inhibited consequent destabilization of junctional protein complexes and intercellular gap formation. The interaction of thrombin with protease activated receptor-1 activates the Rho A guanosine triphosphate (GTP)ase-myosin light chain (MLC) phosphorylation signaling axis, leading to actin cytoskeleton changes. This signaling pathway was effectively inhibited by dabigatran in endothelial cells. Consistently, the number of phosphorylated MLC-positive cells was significantly decreased in ischemic tissue of rat brains. These results indicate dabigatran blocks the ability of thrombin to induce vascular permeability and the resulting underlying signaling cascade in endothelial cells. Our findings provide evidence that dabigatran may confer a lower risk of intracerebral hemorrhage by preserving endothelial barrier integrity.

TC1(C8orf4) correlates with Wnt/beta-catenin target genes and aggressive biological behavior in gastric cancer.

PURPOSE: We have recently reported that TC1(C8orf4), a small protein present in vertebrates, functions as a novel regulator of the Wnt/beta-catenin pathway. TC1 up-regulates beta-catenin target genes that are implicated in the aggressive behavior of cancers. Our aim was to investigate the clinical and pathobiological relevance of TC1 in gastric cancer. EXPERIMENTAL DESIGN: The expression of TC1 was analyzed using tissue microarray in correlation with clinicopathologic variables and beta-catenin target genes in 299 gastric cancers. The biological effects of TC1 on Matrigel invasiveness and the proliferation of cancer cells were analyzed. TC1 expression was analyzed in gastric cancer cells after serial peritoneal implantation in nude mice. RESULTS: TC1 expression was present in 111 carcinomas (37.1%), correlating with tumor stage (P < 0.002), poor differentiation (P < 0.001), lymphatic infiltration (P < 0.005), and lymph node metastasis (P < 0.006). TC1 also correlated with poor survival in diffuse type carcinomas (P < 0.0001), and even in patients with lymph node metastasis (P < 0.0014). TC1 also correlated with the expression of beta-catenin target genes including laminin gamma2, metalloproteinase-7 and metalloproteinase-14, cyclin D1, c-Met, and CD44. TC1 enhanced Matrigel invasiveness and proliferation, supporting its role in the aggressive biological behavior of cancers. The expression of TC1 increased in MKN45 cells after serial peritoneal seeding in nude mice. CONCLUSIONS: Our data suggests that TC1 coordinates the up-regulation of Wnt/beta-catenin target genes that are implicated in the aggressive biological behavior of cancers. The strong clinical relevance, even in patients with lymph node metastasis, suggested that TC1 could be a potential therapeutic target of advanced gastric cancers.

Gingerenone A, a polyphenol present in ginger, suppresses obesity and adipose tissue inflammation in high-fat diet-fed mice.

SCOPE: Ginger exerts protective effects on obesity and its complications. Our objectives here are to identify bioactive compounds that inhibit adipogenesis and lipid accumulation in vitro, elucidate the anti-obesity effect of gingerenone A (GA) in diet-induced obesity (DIO), and investigate whether GA affects adipose tissue inflammation (ATI). METHODS AND RESULTS: Oil red O staining showed that GA had the most potent inhibitory effect on adipogenesis and lipid accumulation in 3T3-L1 cells among ginger components tested at a single concentration (40 µM). Consistent with in vitro data, GA attenuates DIO by reducing fat mass in mice. This was accompanied by a modulation of fatty acid metabolism via activation of AMP-activated protein kinase (AMPK) in vitro and in vivo. Additionally, GA suppressed ATI by inhibiting macrophage recruitment and downregulating pro-inflammatory cytokines. CONCLUSION: These results suggest that GA may be used as a potential therapeutic candidate for the treatment of obesity and its complications by suppressing adipose expansion and inflammation.

[Drinking pattern, problem related drinking, perceived stress, ways of coping, and symptoms of stress of the female university students].

PURPOSE: The purpose of this study was to identify the relationship among problem related drinking, perceived stress, ways of coping, and symptoms of stress of the college women. METHOD: Data was collected by questionnaires from 436 the College Women in S City. It was analyzed using descriptive statistics, Pearson correlation coefficients. RESULT: Three point forty -four of the subject had problem-related drinking, 92.43% were experienced alcohol drinking. The level of perceived stress(M=1.48) showed moderate, and symptoms of stress(M=1.34) showed below. The problem-related drinking showed significant positive correlation with perceived stress(r=.10, p=.03), emotion-oriented coping(r=.13, p=.00), and symptoms of stress(r=.23, p=.03). CONCLUSION: Data from this study suggest that perceived stress, ways of coping, and symptoms of stress are significant influencing factors on problem-related drinking in the Female University Students.

Circulating TNF receptors are significant prognostic biomarkers for idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (iMN) is a common cause of nephrotic syndrome in adults. A biomarker to accurately indicate the severity of iMN and predict long-term prognosis is insufficient. Here, we evaluated the clinical significance of circulating tumor necrosis factor receptors (cTNFRs) as prognostic biomarkers of iMN with nephrotic syndrome. A total of 113 patients with biopsy-proven iMN and 43 healthy volunteers were enrolled in this study. Ninety patients with iMN had nephrotic range proteinuria. Levels of cTNFRs were measured by using serum samples collected at the time of initial diagnosis. Levels of cTNFRs were higher in the patients with nephrotic syndrome than in those with subnephrotic range proteinuria or in the healthy volunteers (P for trend <0.001). Estimated glomerular filtration rate and proteinuria tended to worsen as the cTNFRs levels increased. Having a cTNFR1 level within the highest tertile was a significant risk factor for renal progression after adjustment, in comparison with the other tertiles (hazard ratio [HR], 3.39; 95% confidence interval [95% CI], 1.48-7.78; P = 0.004). The cTNFR2 level within the highest tertile also significantly increased the risk of renal progression (HR, 3.29; 95% CI, 1.43-7.54; P = 0.005). Renal tubular TNFRs expression was associated with cTNFRs level. However, the cTNFRs levels were not associated with autoantibody against phospholipase A2 receptor reactivity/levels or treatment response. This study demonstrated that cTNFRs levels at the time of initial diagnosis could predict renal progression in patients with iMN.

Thrombolytic effects of the snake venom disintegrin saxatilin determined by novel assessment methods: a FeCl3-induced thrombosis model in mice.

Saxatilin, a novel disintegrin purified and cloned from the venom of the Korean snake Gloydius saxatilis, strongly inhibits activation and aggregation of platelets. Glycoprotein (GP) IIb/IIIa receptor antagonists can resolve thrombus, so saxatilin might also have thrombolytic effects. We investigated the thrombolytic effects of saxatilin in mice using a ferric chloride-induced carotid arterial thrombosis model. Thrombotic occlusion and thrombus resolution were evaluated quantitatively by measuring blood flow in the carotid artery with an ultrasonic flow meter and calculating the degree of flow restoration on a minute-by-minute basis; results were confirmed by histological examination. Saxatilin dissolved thrombi in a dose-dependent manner. Saxatilin at 5 mg/kg restored blood flow to baseline levels. As saxatilin dose increased, time to recanalization decreased. A bolus injection of 10% of a complete dose with continuous infusion of the remaining dose for 60 minutes resulted in effective recanalization without reocclusion. The thrombolytic effect of saxatilin was also demonstrated in vitro using platelet aggregometry by administering saxatilin in preformed thrombi. Bleeding complications were observed in 2 of 71 mice that received saxatilin. Fibrin/fibrinogen zymography and platelet aggregometry studies indicated that saxatilin does not have fibrinolytic activity, but exerted its action on platelets. Integrin-binding assays showed that saxatilin inhibited multiple integrins, specifically α2bß3 (GP IIb/IIIa), α5ß1, αvß3, αvß1, and αvß5, which act on platelet adhesion/aggregation. Saxatilin inhibited multiple integrins by acting on platelets, and was safe and effective in resolving thrombi in mice.

Plasma osteoprotegerin levels increase with the severity of cerebral artery atherosclerosis.

OBJECTIVES: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and suggested as a marker of atherosclerosis. We investigated whether plasma OPG levels were associated with the presence and severity of cerebral atherosclerosis. DESIGN AND METHODS: We used an enzyme-linked immunosorbent assay to measure the plasma OPG levels of 107 patients with acute cerebral infarction. We compared the plasma OPG levels according to the presence and number of arteries with cerebral atherosclerosis (≥ 50% stenosis). RESULTS: Of 107 patients, 73 (68.2%) had cerebral atherosclerosis. OPG levels were increased in patients with cerebral atherosclerosis (374.69 ± 206.48 vs 261.17 ± 166.91 pg/mL, p=0.006). OPG levels showed positive correlation with the number of cerebral arteries with atherosclerosis (Spearman's rho=0.342, p<0.001). After adjustment for vascular risk factors, OPG>229.9 pg/mL was independently associated with the presence [OR 4.61, 95% CI 1.57-13.55, p=0.005, binary logistic regression] of cerebral atherosclerosis and number [OR 3.20, 95% CI 1.26-8.12, p=0.014, ordinal logistic regression] of arteries with cerebral atherosclerosis. CONCLUSIONS: Plasma OPG levels were significantly associated with the presence and severity of cerebral atherosclerosis. This finding suggests that plasma OPG might have a role in cerebral atherosclerosis.

Gene expression profiling of anti-GBM glomerulonephritis model: the role of NF-kappaB in immune complex kidney disease.

BACKGROUND: Immune complexes may cause an irreversible onset of chronic renal disease. Most patients with chronic renal disease undergo a final common pathway, marked by glomerulosclerosis and interstitial fibrosis. We attempted to draw a molecular map of anti-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology. METHODS: Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry. RESULTS: Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) < 0.05] were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including interleukin (IL)-1 and IL-6, were identified within 3 days of disease onset. After 7 days, tissue remodeling response was prominent with highly induced extracellular-matrix (ECM) genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. Tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) pathway were consistently activated along the entire disease progression, inducing various target genes like complement 3, IL-1b, IL-6, Traf1, and Saa1. CONCLUSION: We made a large-scale gene expression time table for mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.