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ObjectivesTo examine whether urinary excretion of cysteine-rich protein 61 (Cyr61), an acknowledged proinflammatory factor in kidney pathologies, increases in chronic kidney disease (CKD) and is associated with subsequent rapid kidney function decline.DesignAn observational cohort study.SettingIn the nephrology outpatient clinics of a tertiary hospital in Taiwan.ParticipantsWe enrolled 138 adult CKD outpatients (n=12, 32, 18, 18, 29 and 29 in stages 1, 2, 3a, 3b, 4 and 5 CKD, respectively) between February and October 2014 and followed them for 1 year. Their mean age was 60.46±13.16 years, and 51 (37%) of them were women.Primary outcome measuresUrinary Cyr61 levels were measured by ELISA. Rapid kidney function decline was defined as an estimated glomerular filtration rate (eGFR) decline rate ≥ 4 mL/min/1.73 m2/year or developing end-stage renal disease during subsequent 3-month or 1-year follow-up period. Models were adjusted for demographic and clinical variables.ResultsThe urine Cyr61-to-creatinine ratio (UCyr61CR) increased significantly in patients with stage 4 or 5 CKD. Multivariable linear regression analysis showed that log(UCyr61CR) was positively correlated with log(urine protein-to-creatinine ratio) (pConclusionsElevated urinary Cyr61 excretion is associated with rapid short-term kidney function deterioration in patients with CKD. Measuring urinary Cyr61 excretion is clinically valuable for monitoring disease trajectory and may guide treatment planning.

In adults, membranous nephropathy (MN) is a major cause of nephrotic syndrome. However, the etiology of approximately 75% of MN cases is idiopathic. Secondary causes of MN are autoimmune diseases, infection, drugs, and malignancy. The pathogenesis of MN involves formation of immune complex in subepithelial sites, but the definite mechanism is still unknown. There are three hypotheses about the formation of immune complex, including preformed immune complex, in situ immune-complex formation, and autoantibody against podocyte membrane antigen. The formation of immune complex initiates complement activation, which subsequently leads to glomerular damage. Recently, the antiphospholipase A2 receptor antibody was found to be associated with idiopathic MN. This finding may be useful in the diagnosis and prognosis of MN. The current treatment includes best supportive care, which consists of the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, lipid-lowering agents, and optimal control of blood pressure. Immunosuppressive agents should be used for patients who suffer from refractory proteinuria or complications associated with nephrotic syndrome. Existing evidence supports the use of a combination of steroid and alkylating agents. This article reviews the epidemiology, pathogenesis, diagnosis, and the treatment of MN.

Fibrosis of the peritoneal cavity remains a serious, life-threatening problem in the treatment of kidney failure with peritoneal dialysis. The mechanism of fibrosis remains unclear partly because the fibrogenic cells have not been identified with certainty. Recent studies have proposed mesothelial cells to be an important source of myofibroblasts through the epithelial–mesenchymal transition; however, confirmatory studies in vivo are lacking. Here, we show by inducible genetic fate mapping that type I collagen–producing submesothelial fibroblasts are specific progenitors of α-smooth muscle actin–positive myofibroblasts that accumulate progressively in models of peritoneal fibrosis induced by sodium hypochlorite, hyperglycemic dialysis solutions, or TGF-β1. Similar genetic mapping of Wilms’ tumor-1–positive mesothelial cells indicated that peritoneal membrane disruption is repaired and replaced by surviving mesothelial cells in peritoneal injury, and not by submesothelial fibroblasts. Although primary cultures of mesothelial cells or submesothelial fibroblasts each expressed α-smooth muscle actin under the influence of TGF-β1, only submesothelial fibroblasts expressed α-smooth muscle actin after induction of peritoneal fibrosis in mice. Furthermore, pharmacologic inhibition of the PDGF receptor, which is expressed by submesothelial fibroblasts but not mesothelial cells, attenuated the peritoneal fibrosis but not the remesothelialization induced by hypochlorite. Thus, our data identify distinctive fates for injured mesothelial cells and submesothelial fibroblasts during peritoneal injury and fibrosis.

Blood pressure control with renin-angiotensin system (RAS) blockade has remained the gold standard for treating patients with proteinuric chronic kidney disease (CKD) up to date. Nevertheless, RAS blockade slows but does not halt the progression of kidney disease, thus highlighting the need to search for additional therapeutic approaches. The nonselective phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) is an old drug that exhibits prominent anti-inflammatory, anti-proliferative and anti-fibrotic activities both in vitro and in vivo. Studies in human subjects have shown that PTX monotherapy decreases urinary protein excretion, and add-on therapy of PTX to background RAS blockade additively reduces proteinuria in patients with CKD of various etiology. More recent studies find that PTX combined with RAS blockade delays the decline of glomerular filtration rate in diabetic patients with mild to moderate CKD, and reduces the risk of end-stage renal disease in diabetic and non-diabetic patients in late stage of CKD with high proteinuria levels. In this review, we update the clinical trial results of PTX as monotherapy, or in conjunction or in comparison with RAS blockade on patients with proteinuria and CKD, and propose a mechanistic scheme explaining the renoprotective activities of this drug.

Background/PurposeSeveral studies have shown the renoprotective effects of pentoxifylline in the treatment of chronic kidney disease (CKD). This study was conducted to examine whether there was an increased benefit of including pentoxifylline with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the treatment of CKD.MethodsA single-center retrospective analysis was conducted. A total of 661 Stage 3B-5 CKD patients who received ACEI or ARB treatment were recruited. The patients were divided into the pentoxifylline use group and the no pentoxifylline group. Renal survival analysis of the two groups was compared. Subgroup analysis was performed by dividing the patients into lower [urine protein to creatinine ratio (UPCR)

Pericytes have been identified as the major source of precursors of scar-producing myofibroblasts during kidney fibrosis. The underlying mechanisms triggering pericyte-myofibroblast transition are poorly understood. Transforming growth factor β-1 (TGF-β1) is well recognized as a pluripotent cytokine that drives organ fibrosis. We investigated the role of TGF-β1 in inducing profibrotic signaling from epithelial cells to activate pericyte-myofibroblast transition. Increased expression of TGF-β1 was detected predominantly in injured epithelium after unilateral ureteral obstruction, whereas downstream signaling from the TGF-β1 receptor increased in both injured epithelium and pericytes. In mice with ureteral obstruction that were treated with the pan anti–TGF-β antibody (1D11) or TGF-β receptor type I inhibitor (SB431542), kidney pericyte-myofibroblast transition was blunted. The consequence was marked attenuation of fibrosis. In addition, epithelial cell cycle G2/M arrest and production of profibrotic cytokines were both attenuated. Although TGF-β1 alone did not trigger pericyte proliferation in vitro, it robustly induced α smooth muscle actin (α-SMA). In cultured kidney epithelial cells, TGF-β1 stimulated G2/M arrest and production of profibrotic cytokines that had the capacity to stimulate proliferation and transition of pericytes to myofibroblasts. In conclusion, this study identified a novel link between injured epithelium and pericyte-myofibroblast transition through TGF-β1 during kidney fibrosis.

Summary BackgroundandobjectivesRelativelylittleisknownaboutthelong-termoutcomesofdifferenthistologictypesof primary glomerulonephritis in Asian populations. Design, setting, participants, & measurements From 1993 to 2006, 987 patients undergoing renal biopsy were studied, and 580 patients (mean age=44.4 years, male=58.5%) with the four most common forms of glomerulonephritis (membranous nephropathy, focal and segmental glomerulosclerosis,IgA nephropathy, and minimal change disease) were selected for analysis. Median follow-up period was 5.9 (interquartile range=5.7) years. Results The focal and segmental glomerulosclerosis group displayed the highest incidence of ESRD (25.8%) and the fastest decline of estimated GFR (4.6 ml/min per 1.73 m 2 per year). The IgA nephropathy group also had a higher rate of ESRD than the membranous nephropathy patients (19.2% versus 4.3%, P,0.001). In contrast, the membranous nephropathy group exhibited an overall death rate similar to the focal and segmental glomerulosclerosis group (17.2% versus 14.4%) but higher than the IgA nephropathy and minimal change disease patients (4.6% and 3.7%, respectively, P,0.001). The most powerful predictor for ESRD was focal and segmental glomerulosclerosis, whereas the strongest predictor for all-cause mortality was membranous nephropathy with higher proteinuria. Protectors against ESRD included male sex and higher hemoglobin. Conclusions Most predictors for ESRD and overall mortality found in this ethnic Chinese cohort were similar to other studies. However, some risk factors linked with distinct glomerular pathologies displayed differential clinical outcomes. Clin J Am Soc Nephrol 7: ccc–ccc, 2012. doi: 10.2215/CJN.04500511

BACKGROUND Hemodialysis patients suffer from poor quality of life and survival. A retrospective cohort study was performed to examine the sex differences in self-reported quality of life and mortality in a Taiwanese hemodialysis cohort. METHODS A total of 816 stable hemodialysis patients were included. Patients completed two questionnaires: the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0) to assess health-related quality of life (HRQoL) and the Beck Depression Inventory (BDI, Chinese Version) to assess depressive mood. Mortality outcomes were recorded for a seven-year follow-up period. RESULTS After adjustment for confounding factors, women had significantly higher BDI scores (P=.003), lower physical functioning (P

Pericytes are the major source of scar-producing myofibroblasts following kidney injury; however, the mechanisms of this transition are unclear. To clarify this, we examined Collagen 1 (α1)-green fluorescent protein (GFP) reporter mice (pericytes and myofibroblasts express GFP) following ureteral obstruction or ischemia–reperfusion injury and focused on the role of platelet-derived growth factor (PDGF)-receptor (PDGFR) signaling in these two different injury models. Pericyte proliferation was noted after injury with reactivation of α-smooth muscle actin expression, a marker of the myofibroblast phenotype. PDGF expression increased in injured tubules, endothelium, and macrophages after injury, whereas PDGFR subunits α and β were expressed exclusively in interstitial GFP-labeled pericytes and myofibroblasts. When PDGFRα or PDGFRβ activation was inhibited by receptor-specific antibody following injury, proliferation and differentiation of pericytes decreased. The antibodies also blunted the injury-induced transcription of PDGF , transforming growth factor β1 , and chemokine CCL2. They also reduced macrophage infiltration and fibrosis. Imatinib, a PDGFR tyrosine kinase inhibitor, attenuated pericyte proliferation and kidney fibrosis in both fibrogenic models. Thus, PDGFR signaling is involved in pericyte activation, proliferation, and differentiation into myofibroblasts during progressive kidney injury. Hence, pericytes may be a novel target to prevent kidney fibrosis by means of PDGFR signaling blockade.

Existing chronic kidney disease (CKD) is among the most potent predictors of postoperative acute kidney injury (AKI). Here we quantified this risk in a multicenter, observational study of 9425 patients who survived to hospital discharge after major surgery. CKD was defined as a baseline estimated glomerular filtration rate45 ml/min per 1.73 m(2). AKI was stratified according to the maximum simplified RIFLE classification at hospitalization and unresolved AKI defined as a persistent increase in serum creatinine of more than half above the baseline or the need for dialysis at discharge. A Cox proportional hazard model showed that patients with AKI-on-CKD during hospitalization had significantly worse long-term survival over a median follow-up of 4.8 years (hazard ratio, 1.7) [corrected] than patients with AKI but without CKD.The incidence of long-term dialysis was 22.4 and 0.17 per 100 person-years among patients with and without existing CKD, respectively. The adjusted hazard ratio for long-term dialysis in patients with AKI-on-CKD was 19.8 compared to patients who developed AKI without existing CKD. Furthermore, AKI-on-CKD but without kidney recovery at discharge had a worse outcome (hazard ratios of 4.6 and 213, respectively) for mortality and long-term dialysis as compared to patients without CKD or AKI. Thus, in a large cohort of postoperative patients who developed AKI, those with existing CKD were at higher risk for long-term mortality and dialysis after hospital discharge than those without. These outcomes were significantly worse in those with unresolved AKI at discharge.

Sleep disturbance is common in dialysis patients and is associated with the development of enhanced inflammatory responses. Cognitive-behavioral therapy is effective for sleep disturbance and reduces inflammation experienced by peritoneal dialysis patients; however, this has not been studied in hemodialysis patients. To determine whether alleviation of sleep disturbance in hemodialysis patients also leads to less inflammation, we conducted a randomized controlled interventional study of 72 sleep-disturbed hemodialysis patients. Within this patient cohort, 37 received tri-weekly cognitive-behavioral therapy lasting 6 weeks and the remaining 35, who received sleep hygiene education, served as controls. The adjusted post-trial primary outcome scores of the Pittsburgh Sleep Quality Index, the Fatigue Severity Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory were all significantly improved from baseline by therapy compared with the control group. The post-trial secondary outcomes of high-sensitive C-reactive protein, IL-18, and oxidized low-density lipoprotein levels significantly declined with cognitive-behavioral therapy in comparison with the control group. Thus, our results suggest that cognitive-behavioral therapy is effective for correcting disorganized sleep patterns, and for reducing inflammation and oxidative stress in hemodialysis patients.

Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-β signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets.

The maintenance of good health-related quality of life (HRQoL) is an important goal for end-stage renal disease (ESRD) patients. Whether hemodialysis (HD) and peritoneal dialysis (PD) have different impacts on HRQoL is a concern shared by both physicians and patients. A comparison study of HRQoL between Taiwanese HD and PD patients was conducted. ESRD patients at 14 hospitals or dialysis centers in northern Taiwan were recruited in this cross-sectional study. The Chinese-language version of the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0) was used to evaluate HRQoL. Ordinal regression analyses were used to explore the independent association between HRQoL scores and dialysis modality. By Bonferroni correction test, a P value of

Background: Dialysis patients with uremic pruritus have worse outcomes. However, the pathophysiology of the high mortality in these patients remains inconclusive except for links with calcium/phosphate imbalance and sleep disturbance. Whether inflammation, an outcome predictor in dialysis patients, plays a role is unknown. Methods: This prospective study included 321 chronic hemodialysis (HD) patients ( >3 months) for survival analysis. A visual analog scale (VAS) was used to measure the severity of itching, and the patients were divided into four groups: no pruritus (VAS = 0, N = 118), mild (VAS 1–3, N = 76), moderate (VAS 4–7, N = 89) and severe pruritus (VAS 8–10, N = 38). The Pittsburgh Sleep Quality Index (PSQI) was used to define sleep disturbance, while high-sensitive C-reactive protein (hs-CRP) and tumor necrosis factor α (TNF-α) were used to evaluate inflammation. The patients were followed-up for 30 months. Results: Patients with moderate/severe pruritus had higher hs-CRP, but similar TNF-α levels; they also had a worse survival rate ( P = 0.0197, log rank test). By stratifying hs-CRP levels, those with higher hs-CRP had worse survival regardless of the severity of uremic pruritus. In a Cox proportional hazard model, hs-CRP levels and moderate/severe uremic pruritus were independent predictors of mortality after adjusting for age, poor sleeper (PSQI > 5), diabetes, albumin, phosphate, hemoglobin and parathyroid hormone levels and (hs-CRP) × (moderate/severe uremic pruritus) (all P < 0.05). Conclusion: In moderate/severe pruritic HD patients, those with higher hs-CRP suffer from worse overall mortality. Inflammation may bridge uremic pruritus to high mortality, and elevated hs-CRP predicts a worse outcome in this population.

This study evaluated the correlations between spiritual beliefs and health-related quality of life (HRQOL) of hemodialysis (HD) patients in Taiwan. Participants had to complete two questionnaires: the 36-item Short Form Health Survey Questionnaire and the Royal Free Interview for Spiritual and Religious Beliefs. They were then divided into three groups according to their strength of spiritual beliefs—having no, weak, or strong beliefs. Demographic, clinical, and laboratory data among groups were compared. Correlations between spiritual beliefs and HRQOL were then determined by the analysis of covariance and the post hoc Scheffe tests. Six hundred thirty-three patients completed the study. There were more women in the group of patients with strong beliefs (P = 0.005) and more less-educated patients in the group of patients with weak beliefs (P = 0.005). Patients with no or with strong spiritual beliefs had higher role physical (P = 0.01) and social functioning (SF) (P = 0.001) scores than patients with weak beliefs. After adjustment for gender, age, marital status, education, comorbidities, and time on dialysis, patients with no or with strong spiritual beliefs were found to have higher SF scores (P = 0.02) than patients with weak beliefs. HD patients with no or strong spiritual beliefs had higher SF HRQOL than those with weak spiritual beliefs.

Background. Increased inflammation has been noted in sleep disorder patients with normal renal function. However, the relationship between sleep quality and circulating inflammatory markers has not been previously studied in haemodialysis (HD) patients. Methods. A total of 114 HD end-stage renal disease patients receiving maintenance HD for >3 months were included in this study. Pittsburgh Sleep Quality Index (PSQI) was used to measure individual’s sleep quality. Based on the global PSQI score, patients were divided into groups of good sleepers (PSQI < 5) and bad sleepers (PSQI ≥ 5). Results. Twenty-three patients (20.2%) were classified as good sleepers and 91 patients (79.8%) were bad sleepers. Bad sleepers have significantly higher serum hsCRP level and lower serum phosphate level (all P < 0.05). The global PSQI score, or worse sleep quality are positively correlated with serum triglyceride level, high-sensitivity C-reactive protein(hsCRP)level,IL-1βlevelandnegativelycorrelated with the haemoglobin and phosphate level. In the multivariable linear regression model, levels of hsCRP (β = 0.209, P = 0.029) and triglyceride (β = 0.212, P = 0.025) were both significant independent predictors for the global PSQI score. Conclusion. Our study demonstrated severe impairment of sleep quality in HD patients and corroborated the role of inflammation in the pathogenesis of sleep disturbance.

Background/Aims: Pentoxifylline (PTX) has been shown to inhibit renal inflammation in a rat model of crescentic glomerulonephritis. The present study investigated the role of PTX in renal fibrosis in rats with crescentic glomerulonephritis. Methods: A rat model of accelerated anti-glomerular basement membrane glomerulonephritis was induced and treated with PTX or vehicle control for 3, 7, 14 and 28 days. The therapeutic effect and mechanism of PTX on renal fibrosis were examined by Northern blot and immunohistochemistry. Results: Diseased rats treated with vehicle control developed a severe crescentic glomerulonephritis with progressive renal fibrosis identified by a marked accumulation of α-SMA+ myofibroblasts and collagen matrix. This was associated with tubular epithelial-myofibroblast transition as evident by de novo expression of α-SMA and a loss of E-cadherin on damaged tubular epithelial cells. Further studies revealed that severe renal fibrosis was associated with upregulation of renal TGF-β1 and activation of TGF-β/Smad signaling, which was blocked by treatment with PTX. Conclusions: PTX may be an anti-fibrosis agent capable of inhibiting renal fibrosis in a rat model of crescentic glomerulonephritis. Blockade of TGF-β1 expression and Smad2/3 activation may be a mechanism by which PTX inhibits renal fibrosis.

The peritoneum is subject to alterations in the life-long course of peritoneal dialysis (PD). Studies of the parietal peritoneum by non-invasive ultrasonography in PD patients are limited. We hypothesize that a prolonged PD duration is associated with a thicker peritoneum on ultrasonography and alterations in Doppler indexes of mesenteric vessels.We recruited two groups of patients, 18 who had7 years of PD and 18 who had12 months of PD. We excluded patients with active peritonitis, history of major abdominal surgery, cirrhosis or malignancy. We measured the sonographic thickness of the parietal peritoneum and Doppler indexes of mesenteric vessels by trans-abdominal ultrasonography at two PD units in Taiwan.We found no significant difference between two groups of PD patients in peritoneal thickness and in Doppler indexes. However, our univariate and multivariate analysis indicated that peritoneal thickness is associated with peritoneal transport characteristics (dialysate/plasma creatinine) but not with age, duration of dialysis, body height, body weight or Doppler index. The peritoneum is significantly thicker in rapid transporters than in slow transporters (RUQ: 0.59 +/- 0.40 mm versus 0.27 +/- 0.29 mm, P = 0.01; LUQ: 0.60 +/- 0.40 mm versus 0.27 +/- 0.32 mm, P = 0.016; LQ: 1.07 +/- 0.85 mm versus 0.48 +/- 0.53 mm, P = 0.026). In addition, rapid transporters have a marginally lower Doppler resistive index of the superior mesenteric artery (0.87 +/- 0.08 versus 0.90 +/- 0.10, P = 0.028).Our data showed that peritoneal thickening is not inevitable in long-term PD patients. Sonographic thickness in the parietal peritoneum is associated with transport characteristics. Rapid transporters have a significantly thicker peritoneum. The Doppler index of mesenteric vessels had no association with PD duration or transport characteristics. Trans-abdominal ultrasonography is non-invasive and useful in evaluating peritoneal characteristics of PD patients.

Background The prevalence of sexual dysfunction among male haemodialysis patients is high. Sexual dysfunction is composed of both physiological and psychological factors. However, the role of psychological depression is still obscure. Methods A multicentre cross-sectional study of 411 male haemodialysis patients was conducted to define the determinants of sexual dysfunction. Mid-week pre-dialytic biochemical and haematological parameters were obtained. All patients were required to complete three questionnaires by themselves: (i) the International Index of Erectile Function (IIEF, Chinese version); (ii) the Beck Depression Inventory (BDI, Chinese version) and (iii) the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0). Results In total, 154 male patients completed the IIEF questionnaire. Their mean age was 50.2 +/- 10.7 years. A linear multivariable regression analysis demonstrated advanced age, diabetes and the presence of depressive symptoms to be independently associated with sexual dysfunction. Subjects with sexual dysfunction had significantly lower quality of life scores. Conclusions The presence of depressive symptoms, highly prevalent in haemodialysis patients, is an independent factor of sexual dysfunction in male haemodialysis patients. In a comprehensive approach to the management of sexual dysfunction, a thorough evaluation of psychological depression must be included.

Background. After long-term treatment with continuous ambulatory peritoneal dialysis (CAPD), some patients may develop peritoneal fibrosis. Peritoneal mesothelial cells (PMCs) participate in the inflammatory reactions in the peritoneal cavity, and transforming growth factor-b1 (TGF-b1) and interleukin-1b (IL-1b) are involved in peritoneal fibrosis. Diltiazem is used frequently in patients with CAPD to treat hypertension. The objectives of this study were to examine the effects of diltiazem on collagen- and IL-1b-induced TGF-b1 production on human PMCs and the signalling pathway of diltiazem in this induction. Methods. Human PMCs were cultured from the enzymatic disaggregation of human omentum. Collagen synthesis was measured by [ 3 H]proline incorporation into pepsin-resistant, salt-precipitated collagen. The expression of collagen I and III, and TGF-b1 mRNA was evaluated by northern blotting. The production of TGF-b1 by human PMCs was measured by immunoassay. The changes of intracellular calcium level after adding Fura-2-AM were measured by fluorescence spectrophotometry. Western blotting was used to assess mitogen-activated protein kinase (MAPK) signalling proteins. Results. We found that diltiazem (

Background/Purpose: Pauci-immune glomerulonephritis (GN) is an important cause of crescentic GN, acute renal failure and mortality. However, data are limited on the clinical presentation and outcome in antineutrophil cytoplasmic antibody (ANCA) negative patients, especially in Asians. Methods: This retrospective study analyzed medical records and pathology slides of patients who received renal biopsy between February 1998 and October 2004. Enzyme-linked immunosorbent assay was used routinely for ANCA testing in all patients. Results: Among 637 patients with biopsy-proven GN included in this study, 88 (13.8%) had glomerular crescent formation. Among them, pauci-immune crescentic glomerulonephritis (PICGN) (42 patients, 47.2%) and lupus nephritis (25 patients, 28.4%) were the most common pathologic diagnoses. Lupus patients were younger (p=0.028), while PICGN patients had more chronic lesions (p＜0.001), extensive glomerular crescents (p＜0.001), less severe proteinuria (p＜0.001) and poorer renal survival (p=0.0017). Among the PICGN patients, 62.5% had a positive ANCA test, 80% had myeloperoxidase-ANCA and 20% had proteinase-3-ANCA. Subgroup analysis showed that ANCA negativity was associated with less crescent formation (p＜0.001) but more chronic glomerular lesions (p＜0.001) and a trend toward worse renal outcome (p=0.055). Conclusion: This study illustrates the necessity for pathologic diagnosis of pauci-immune GN despite ANCA negativity. The poor prognosis associated with ANCA negativity in this study may be partly due to delayed diagnosis since these patients frequently lacked systemic involvement.

Peritoneal dialysis (PD) has been established as a main renal replacement therapy for approximately 20 years. However, long-term peritoneal exposure to high glucose and other unphysiologic contents in the PD solution may potentiate the development of peritoneal fibrosing syndrome (PFS) in PD patients. PFS is composed of a wide spectrum of peritoneal alterations, which has been observed in PD patients. Molecular studies have shown that the fibrogenic effect of peritoneal mesothelial cells and the accompanying accumulation of extracellular matrix in the peritoneum are key events leading to PFS. In this review, we highlight the impact of PFS and its pathogenetic factors, including bioincompatible PD solution, multidisciplinary inflammatory mediators, and stimulatory cytokines in the peritoneal cavity. Current therapeutic strategies based on both clinical and basic evidence for the prevention or treatment of PFS are also reviewed.

Sexual dysfunction in female hemodialysis patients: A multicenter study. Background Sexual function is one aspect of physical functioning. Sexual dysfunction, no matter the etiology, could cause distress. In female hemodialysis patients, sexual problems have often been neglected in clinical performance and research. Methods We conducted this study by use of self-reported questionnaires. A total of 578 female hemodialysis patients in northern Taiwan were included in this study. Demographic data, comorbid diseases, medications in use, biochemical, and hematologic parameters were analyzed. All patients were asked to complete by themselves three questionnaires: ( 1 ) the Index of Female Sexual Function (IFSF) to assess sexual function; ( 2 ) the Beck Depression Inventory (BDI) (Chinese version) to rate the severity of depressive symptoms; and ( 3 ) the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0) to survey their quality of life. Results A total of 138 female patients were enrolled into further analysis. The mean age was 48.7 ± 11.2 years old. The mean IFSF score was 24.5 ± 9.3. Age, BDI score, and serum triglyceride levels were the independent factors of dysfunction in each sexual functional dimension. Patients with higher IFSF scores had significantly higher scores in physical functioning and mental health ( P = 0.007 and 0.018, respectively). Patients with higher intercourse satisfaction had significantly higher general health scores ( P = 0.001). Conclusion Sexual dysfunction is frequent in the female hemodialysis population. It is strongly associated with increasing age, dyslipidemia, and depression. The subjects with sexual dysfunction had poorer quality of life. The diagnosis and treatment of sexual dysfunction should be included in the clinical assessment.

A 63-year-old woman of South Asian origin, a Gujerati-speaking Hindu, was admitted 5 years ago to the renal unit at Leicester General Hospital for further evaluation of chronic kidney disease (CKD). She was born in India, moved to East Africa as a child, and migrated from Malawi to the United Kingdom in 1972. Her medical history included four uneventful pregnancies. She has no history of diabetes mellitus or hypertension. Three of her cousins had developed type 2 diabetes in the fourth decade of life, and her deceased aunt developed end-stage renal disease (ESRD) in the seventh decade of life and required renal replacement therapy (RRT). Three months before admission, the patient had reported increasing tiredness and was found to have a normochromic normocytic anemia, which was unresponsive to oral iron supplementation. On admission she reported continuing tiredness and breathlessness on moderate exertion, with no angina, cough, sputum, or wheeze. She reported nocturia for the previous 5 years but no other urinary symptoms. A review of systems was otherwise

Current interventions with proven efficacy, such as glycemic and blood pressure control, dietary protein restriction, and angiotensin II blockade, slow the progression of chronic kidney disease (CKD); however, whether long-term cessation of CKD progression is possible remains unclear. Because of the pathogenetic complexity of this condition, multidrug interventions with the least adverse effects should be investigated as the next step in attempts to stop CKD progression. Pentoxifylline, a non-selective phosphodiesterase inhibitor with indiscernible toxicity, exerts potent inhibitory effects against cell proliferation, inflammation, and extracellular matrix accumulation, all of which play important roles in CKD progression. Pentoxifylline monotherapy markedly reduces proteinuria in patients with membranous nephropathy. Moreover, limited human studies have proven pentoxifylline efficacy in reducing proteinuria in patients with diabetes receiving angiotensin-converting enzyme inhibitors, and in patients with nephrotic syndrome secondary to lupus nephritis despite immunosuppressive therapy. Further clinical trials are necessary to examine whether pentoxifylline can improve renal outcomes in patients receiving interventions of proven efficacy.

Almost all forms of chronic kidney disease progressing to end-stage kidney failure are characterized by diffuse fibrosis, a final common pathway converging from multiple pathogenetic networks regardless of the initial injury. Four principal interventions including glycaemic and blood pressure control, dietary protein restriction, and angiotensin II blockade have been proven to slow progression of diabetic and/or non-diabetic chronic kidney disease. However, the ultimate solution to halt disease progression in the long term is still pending. Because of the pathogenetic complexity of kidney disease, multidrug intervention with the least side-effects should, without doubt, be the next step to stop kidney disease progression. Animal and cellular studies have demonstrated the rationale for pentoxifylline (i.e. its effects against cell proliferation, inflammation, and extracellular matrix accumulation) in the treatment of chronic kidney disease induced by immune- or non-immune-mediated mechanisms. Limited human studies have proven its efficacy in reducing proteinuria in patients with diabetes receiving angiotensin-converting enzyme inhibitors, and in patients with nephrotic syndrome refractory to conventional immunosuppressive therapy. Moreover, monotherapy with pentoxifylline markedly reduces proteinuria in patients with membranous nephropathy. Further studies are required to examine whether pentoxifylline can improve the renal outcome in patients receiving interventions with proven efficacy.

BACKGROUND Crescentic glomerulonephritis is a rapidly progressive form of glomerulonephritis, but treatment remains non-specific. The methylxanthine derivative pentoxifylline (PTX) is a clinically available phosphodiesterase inhibitor with anti-inflammatory and immunoregulatory activities. This study examined whether PTX has beneficial effects in a rat model of anti-glomerular basement membrane (GBM) crescentic glomerulonephritis. METHODS Experimental crescentic glomerulonephritis was induced in Wistar rats by intravenous injection of rabbit anti-rat GBM serum and treated with either vehicle (phosphate-buffered saline) or PTX (0.1 g/kg/day) intravenously on a daily basis. Groups of six animals were euthanized at days 3, 7, 14 or 28 after induction of disease. Effects of PTX on renal function, histology and expression of cytokines, chemokines and adhesion molecules were determined. RESULTS Compared with the vehicle-treated nephritic rats, PTX treatment beginning at the start of the nephritis significantly suppressed mRNA expression of tumour necrosis factor (TNF)-alpha, but not interleukin-1 beta, throughout the course of nephritis. Moreover, PTX decreased renal mRNAs for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and osteopontin (OPN) at all time points examined. These effects were associated with a significant inhibition of macrophage and T-cell infiltration, a reduction of 24-h urinary protein excretion (50-75%, P

BACKGROUND Mesangial cells (MCs) can promote glomerular macrophage accumulation in glomerulonephritis through production of a variety of chemokines. This study investigated the potential of MCs to synthesize CX3CL1/fractalkine, a CX3C chemokine, both in vitro and in acute anti-Thy1 glomerulonephritis in rats. METHODS Anti-Thy1 glomerulonephritis was induced in Wistar rats by a single injection of mouse anti-rat Thy1.1 antibody intravenously. Glomerular mRNAs for CX3CL1/fractalkine, CCL2/monocyte chemoattractant protein (MCP)-1, and their cognate receptors, CX3CR1 and CCR2, were determined by northern blot analysis or reverse-transcription polymerase chain reaction. CX3CL1/fractalkine mRNA and protein expression in vivo was localized by in situ hybridization and immunohistochemistry. Monocytes/macrophages and activated MCs were detected by immunohistochemistry. Regulation of CX3CL1/fractalkine expression in cultured MCs was determined by northern and western blot analysis. RESULTS After induction of anti-Thy1 disease, glomerular CX3CL1/fractalkine mRNA was significantly up-regulated, peaking at 2 h and sustaining into day 5 of the nephritis. A corresponding increase in urinary CX3CL1/fractalkine protein was evident after day 1 of the nephritis, but became more prominent during the MC proliferative phase (days 3-5). Meanwhile, induction of glomerular CCL2/MCP-1 mRNA and urinary CCL2/MCP-1 protein occurred within 24 h, and was barely detectable after day 3 of the nephritis. Urinary CCL2/MCP-1, but not CX3CL1/fractalkine, correlated with glomerular macrophage accumulation (r = 0.936, P

Pentoxifylline (PTX) is a potent inhibitor of mesangial cell proliferation, but its underlying mechanism is poorly understood. Here, we demonstrate that in platelet-derived growth factor (PDGF)-stimulated mesangial cells, PTX causes G1 arrest by down-regulation of cyclin D1 expression, which subsequently attenuates Cdk4 activity. In vivo, PTX similarly reduces cyclin D1 expression in mesangial cells of rats with acute Thy1 glomerulonephritis. The mechanism by which PTX reduces cyclin D1 is also investigated. PTX blocks Akt but not phosphatidylinositol 3-kinase (PI3K) activation in response to PDGF and abrogates cyclin D1 induction by PI3K, suggesting an effect of PTX on Akt itself. Indeed, PTX is capable of blocking the membrane translocation of Akt, and enforced targeting of Akt to cell membrane prevents the inhibition of Akt and cyclin D1 by PTX. Because PTX is known to increase intracellular cAMP levels by inhibiting phosphodiesterase, the role of protein kinase A (PKA) in these events is investigated. The PKA antagonist N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89) abolishes cell proliferation effects of PTX and restores cyclin D1 expression as well as Akt membrane translocation and activation by PDGF, whereas dibutyryl cAMP and forskolin recapitulate the functions of PTX in mesangial cells. In conclusion, our results indicate that PTX, acting through PKA, interferes with PDGF signaling to Akt activation by blocking Akt membrane translocation, thereby inhibiting cyclin D1 expression and mesangial cell proliferation.

SUMMARY: The peritoneal mesothelial cell is a critical component of the peritoneal membrane. The intraperitoneal use of several antibiotics to treat bacterial peritonitis is current clinical practice. Our previous study showed that cephalothin (CPL) and cefotaxime (CFT) have cytotoxic effects on human peritoneal mesothelial cells (HPMC), however, the exact mechanism of cytotoxicity has not been elucidated. In the present study, flow cytometry, TdT-mediated dUTP nick-end labelling (TUNEL) staining and electron microscopy were used to detect the apoptosis of HPMCs. Immunofluorescent staining was used to evaluate the cytochrome c distribution pattern. Western blotting was used to assess apoptotic signalling proteins. We found that CPL (0.5 mg/mL) and CFT (1 mg/mL) induced apoptosis of HPMCs, whereas cefazolin (0.5 mg/mL) and ceftriaxone (0.5 mg/mL) failed to induce apoptosis of HPMCs. While the DNA content of CFT- or CPL-treated cells was reduced, as determined by flow cytometry, cefazolin and ceftriaxone had no such effect. The CFT- or CPL-treated cells displayed the features of apoptosis both under the electron microscope and by using TUNEL staining. However, cefazolin and ceftriaxone produced the same result as the medium controls. Furthermore, CFT and CPL increased the expression of Bax and p53, and caused the translocation of cytochrome c from the mitochondria to the cytoplasm. The HPMC treated by CFT but not by CPL induced the cleavage of procaspase-3 to form active caspase-3. In conclusion, cefotaxime and cephalothin induce apoptosis of HPMCs in vitro. Signal transduction may be through the mitochondrial pathway.

(1) Fractalkine is a CX(3)C chemokine for mononuclear leukocytes that is expressed mainly by vascular cells, and regulated by pro-inflammatory cytokines. This study investigated signal transduction mechanisms by which tumor necrosis factor (TNF)-alpha stimulated fractalkine expression in cultured rat vascular smooth muscle cells (VSMCs), and the modulatory effect of a haemorrheologic agent, pentoxifylline, on its production. (2) TNF-alpha (1-50 ng ml(-1)) stimulated fractalkine mRNA and protein expression in concentration- and time-dependent manners. Pretreatment with calphostin C (0.4 micro M, a selective inhibitor of protein kinase C (PKC), and PD98059 (40 micro M), a specific inhibitor of p42/44 mitogen-activated protein kinase (MAPK) kinase, attenuated TNF-alpha-stimulated fractalkine mRNA and protein expression. In contrast, H-89 (2 micro M), a selective inhibitor of cAMP-dependent protein kinase, wortmannin (0.5 micro M), a selective inhibitor of phosphatidylinositol 3-kinase, and SB203580 (40 micro M), a specific inhibitor of p38 MAPK, had no discernible effect. (3) The ubiquitin/proteosome inhibitors, MG132 (10 micro M) and pyrrolidine dithiocarbamate (200 micro M), suppressed activation of NF-kappaB as well as stimulation of fractalkine mRNA and protein expression by TNF-alpha. (4) TNF-alpha-activated phosphorylation of PKC was blocked by calphostin C, whereas TNF-alpha-augmented phospho-p42/44 MAPK and phospho-c-Jun levels were reduced by PD98059. Neither calphostin C nor PD98059 affected TNF-alpha-induced degradation of I-kappaBalpha or p65 nuclear translocation. (5) Pretreatment with pentoxifylline (0.1-1 mg ml(-1)) decreased TNF-alpha-stimulated fractalkine mRNA and protein expression, which was preceded by a reduction in TNF-alpha-activated phosphorylation of PKC, p42/44 MAPK and c-Jun as well as degradation of I-kappaBalpha and p65/NF-kappaB nuclear translocation. (6) These data indicate that activation of PKC, p42/44 MAPK kinase, and NF-kappaB are involved in TNF-alpha-stimulated fractalkine production in VSMCs. Down-regulation of the PKC, p42/44 MAPK, and p65/NF-kappaB signals by PTX may be therapeutically relevant and provide an explanation for the anti-fractalkine effect of this drug.

Tumor necrosis factor-α stimulates fractalkine production by mesangial cells and regulates monocyte transmigration: Down-regulation by cAMP. Background Fractalkine is a CX 3 C chemokine for mononuclear cells that has been implicated in the recruitment and accumulation of monocytes seen in glomerular diseases. We investigated the mechanisms by which tumor necrosis factor (TNF)-α stimulates mesangial cell (MC) fractalkine expression, and the effects of MC-derived fractalkine on monocyte transmigration. Methods Cultured rat MCs were incubated with TNF-α, with or without pretreatment with pharmacologic inhibitors of protein kinases or transcriptional factors downstream to TNF-α. Fractalkine mRNA and protein were analyzed by Northern and Western blotting. Translocation of nuclear factor (NF)-κB was evaluated by immunocytochemical staining. Monocyte transmigration was determined by in vitro chemotaxis assay. Results TNF-α stimulated MC fractalkine mRNA as well as cell-bound and soluble protein expression in a dose- and time-dependent manner. The soluble fractalkine was shed from the cell-bound form via metalloproteinase-dependent cleavage, and mediated in part TNF-α–induced monocyte transmigration in vitro. The incubation of MCs with calphostin C [a selective inhibitor of protein kinase C (PKC)] or PD98059 [a selective inhibitor of p42/44 mitogen-activated protein kinase (MAPK) kinase] attenuated TNF-α–stimulated fractalkine mRNA and protein expression. Coincubation of MCs with calphostin C and PD98059 resulted in a synergistic inhibition of TNF-α–stimulated fractalkine mRNA and protein expression. Incubation of MCs with phorbol myristate acetate (PMA) for four hours resulted in an increase in fractalkine mRNA expression that could be suppressed by calphostin C or depletion of PKC by pretreatment with PMA for 24 hours. Further, activation of PKC-depleted MCs with TNF-α stimulated fractalkine mRNA expression that could be blocked by calphostin C. PD 98059, but not calphostin C, inhibited TNF-α–activated phospho-p42/44 MAPK and phospho-c-Jun levels, whereas only calphostin C inhibited TNF-α–activated phosphorylation of PKCζ/ι. The incubation of MCs with MG132, a NF-κB inhibitor, abolished TNF-α–induced degradation of inhibitory protein of NF-κB (I-κB)α, nuclear translocation of NF-κB, and fractalkine expression, without affecting phospho-c-Jun levels. In contrast, curcumin, an activating protein (AP)-1 inhibitor, attenuated TNF-α–stimulated phospho-c-Jun levels and fractalkine expression without discernible effects on TNF-α–induced degradation of I-κBα or NF-κB nuclear translocation. Neither PD 98059 nor calphostin C affected TNF-α–induced degradation of I-κBα or NF-κB nuclear translocation. Additional experiments examining the role of cAMP on MC fractalkine expression showed that the incubation of MCs with TNF-α and either db-cAMP or forskolin attenuated TNF-α–stimulated fractalkine mRNA and protein expression, preceded by attenuation of TNF-α–activated phosphorylation of p42/44 MAPK, and c-Jun, but not phosphorylation of PKCζ/ι or nuclear translocation of NF-κB. Conclusion The present data indicate that TNF-α activation of PKCζ/ι, p42/44 MAPK, c-Jun/AP-1, and p65/NF-κB are involved in TNF-α–stimulated MC fractalkine expression, with the soluble fractalkine mediating in part the TNF-α–induced monocyte transmigration in vitro. Uncoupling of p42/44 MAPK or c-Jun/AP-1 signals may contribute to cAMP inhibition of MC fractalkine expression activated by TNF-α.

Previous studies have reported that pentoxifylline, a phosphodiesterase inhibitor, attenuates experimental mesangial proliferative glomerulonephritis. This study hypothesized that pentoxifylline could also attenuate the renal disease progression in rats with remnant kidney. After 5/6 subtotal nephrectomy, rats developed progressively elevated proteinuria and plasma creatinine, glomerulosclerosis, interstitial inflammation, and fibrosis, all of which were attenuated by 40 to 60% by pentoxifylline. However, the elevated BP was not changed by pentoxifylline. Pentoxifylline reduced the upregulation of monocyte chemoattractant protein-1 gene by 60% in the cortex of remnant kidney, as well as in a dose-dependent manner in the albumin- or angiotensin II-stimulated proximal tubular cells. It also reduced the upregulation of mitogenic and profibrogenic genes by 50%, including platelet-derived growth factor, fibroblast growth factor-2, transforming growth factor-β 1 , connective tissue growth factor, and types I and III collagen in the cortex of remnant kidney. Furthermore, pentoxifylline was found to decrease the numbers of interstitial myofibroblasts by 60% in the cortex of remnant kidney and suppress the proliferation of cultured interstitial fibroblasts. It also reduced the angiotensin II-induced or transforming growth factor-β 1 -induced expression of connective tissue growth factor gene in cultured fibroblasts and mesangial cells. Combining pentoxifylline with an angiotensin-converting enzyme inhibitor, cilazapril, almost completely attenuated the renal disease progression in rats with remnant kidney. In conclusion, pentoxifylline alone can attenuate the chronic renal disease progression. Its combination with cilazapril has the potential to prevent the renal disease progression almost completely.

SUMMARY: Peritoneal fibrosing syndrome (PFS) is composed of a wide spectrum of peritoneal alterations observed in patients under peritoneal dialysis (PD). Long-term peritoneal exposure to unphysiological PD solutions and recurrent bacterial peritonitis had been claimed as the most common causes predisposing to the development of PFS in a PD population. With the advances in molecular research, physicians and pathologists recognized that peritoneal injury and the accompanied accumulation of extracellular matrix (ECM) within the peritoneum are key events leading to PFS. Bioincompatible solution and it's related products, inflammatory mediators, growth factors as well as cytokines in the peritoneal cavity are contributing factors. Therapeutic strategies antagonizing these mediators and/or their downstream intracellular signalling pathways with either drug molecules or gene transfer may have potential for the prevention or treatment of PFS.