Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Background and objectives: Treatment with IFN is rarely associated with nephrotic syndrome and renal biopsy findings of minimal-change disease or FSGS.Design, setting, participants, & measurements: We report 11 cases of collapsing FSGS that developed during treatment with IFN and improved after discontinuation of therapy.Results: The cohort consists of seven women and four men with a mean age of 48.2 yr. Ten of the 11 patients were black. Six patients were receiving IFN-α for hepatitis C virus infection (n = 5) or malignant melanoma (n = 1), three were receiving IFN-β for multiple sclerosis, and two were treated with IFN-γ for idiopathic pulmonary fibrosis. After a mean and median duration of therapy of 4.0 and 12.6 months, respectively, patients presented with acute renal failure (mean creatinine 3.5 mg/dl) and nephrotic-range proteinuria (mean 24-hour urine protein 9.7 g). Renal biopsy revealed collapsing FSGS with extensive foot process effacement and many endothelial tubuloreticular inclusions. Follow-up was available for 10 patients, all of whom discontinued IFN. At a mean of 23.6 months, nine of 10 patients had improvement in renal function, including one with complete remission and two with partial remission. Among the seven patients with available data, mean proteinuria declined from 9.9 to 3.0 g/d. Four of the seven patients were treated with immunosuppression, and there was no detectable benefit.Conclusions: Collapsing FSGS may occur after treatment with IFN-α, -β, or -γ and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions. Optimal therapy includes discontinuation of IFN.FSGS is the most common cause of idiopathic nephrotic syndrome in black patients and may be the most frequent cause of nephrotic syndrome in the general population (1–6). The spectrum of FSGS includes primary forms mediated by a putative circulating or permeability factor and a number of secondary forms caused by such diverse insults as hereditable mutations in podocyte genes, drugs, viral infections, and adaptive responses to reduced renal mass or other hemodynamic stress (1). A variety of histologic variants of FSGS have been identified and can be applied to both primary and secondary forms (7–9). Many secondary forms tend to manifest as particular morphologic subtypes (1).The collapsing variant of FSGS is defined by implosive wrinkling and “collapse” of the glomerular basement membrane associated with hypertrophy and hyperplasia of overlying podocytes (10–12). Collapsing FSGS was mainly described in patients with HIV-associated nephropathy (HIVAN) (13) but also was recognized as a variant of idiopathic FSGS (11,12). Both idiopathic collapsing FSGS and HIVAN are most commonly seen in young black patients (8–12,14). Compared with the usual, most common form of FSGS with discrete segmental scars (FSGS not otherwise specified [FSGS NOS]), collapsing FSGS is distinguished by more severe nephrotic syndrome and renal insufficiency at presentation and a more rapid course to renal failure (8–12,14). Central to the morphogenesis of the collapsing variant is podocyte injury that leads to podocyte dedifferentiation, apoptosis, and proliferation, in part through dysregulation of cell cycle–related proteins (15–19). Podocyte precursor cells from the parietal cell layer may contribute to the glomerular epithelial cell proliferation (20).HIVAN is not the only established secondary cause of collapsing FSGS. Collapsing FSGS has been reported in the setting of Parvovirus B19 infection (21) and in patients with hemophagocytic syndrome (with or without underlying lymphoma) (22). Collapsing FSGS also may follow treatment with pamidronate (23), with 15 cases reported in the medical literature (23,24). In contrast, FSGS NOS has been reported to result from treatment with lithium (25), sirolimus (26), and more recently anabolic steroids (27). Although rare cases of collapsing FSGS also have been reported after treatment with IFN-α (28–30), this therapeutic agent is more commonly associated with minimal-change disease (MCD) (31–38) and FSGS NOS (39–47). We report 11 additional cases of collapsing FSGS that developed during treatment with IFN, including six IFN-α (for hepatitis C virus [HCV] infection or melanoma), three IFN-β (for multiple sclerosis [MS]), and two IFN-γ (for idiopathic pulmonary fibrosis).     

Impact of Age and Overt Proteinuria on Outcomes of Stage 3 to 5 Chronic Kidney Disease in a Referred Cohort

Background and objectives: Population-based studies have reported outcomes and risk factors for patients with chronic kidney disease (CKD), defined primarily by decreased estimated GFR (eGFR). They are characterized by old age, low proteinuria level, and stage 3 CKD. However, many patients referred to nephrologists are younger and have overt proteinuria and advanced CKD. This study evaluated the association between outcomes and those factors among referred CKD patients.Design, setting, participants, & measurements: We retrospectively reviewed 461 referred patients with stage 3 to 5 CKD from January 2003 to December 2007. Key outcomes were death and ESRD. Patients were followed from the time of first serum creatinine measurement to December 2009.Results: The median age of subjects was 67.0 years, and median follow-up was 3.2 years. Overt proteinuria was present in 57.0% of subjects. For stage 3, 4, and 5 CKD, cumulative mortality and probability of ESRD at 3 years was 9.5 and 6.5%, 11.2 and 27.8%, and 16.5 and 79.1%, respectively. Using proportional-hazards regression models, age was a determinant for death, whereas overt proteinuria was strongly associated with ESRD. Among stage 3 CKD patients older than 65 years without overt proteinuria, the incidence of death before renal replacement therapy (RRT) was 2.8/100 patient-years and none had ESRD. In patients with advanced CKD and overt proteinuria, the incidence of ESRD was substantially higher than that of death before RRT.Conclusions: Stratification by age, proteinuria level, and CKD stage could predict the competing outcomes of death before RRT and ESRD among CKD patients.The diagnostic classification of chronic kidney disease (CKD) (1) is useful to understand kidney function and risk of complications. Previous studies have demonstrated that CKD increases the risks of cardiovascular morbidity and mortality (2–13). The prevalence of CKD has been shown to be high in population studies (10% to 13%) (14–16), and for CKD patients in the general population, the risk of death, particularly due to cardiovascular disease (CVD), is much higher than that of ESRD requiring renal replacement therapy (RRT) (12–13). Population-based studies have also reported that CKD patients have a mean age of about 70 years (15–18), and most of them had little proteinuria/albuminuria and stage 3 CKD (15–16), primarily defined by decreased estimated GFR (eGFR).However, many patients referred to nephrologists are relatively younger than those in population-based studies, and often have overt proteinuria and advanced CKD (19–20). A small but significant number of those patients should be carefully evaluated and intensively managed by nephrologists. It is important to clarify the prognoses and risk factors for these patients. Japan is an appropriate country for a survival analysis of CKD patients who have undergone nephrology care as it has a generous social-welfare system, kidney screening program, and public medical care insurance; thus almost all patients can receive sufficient care, including RRT (21).In the present study, we investigated outcomes among referred patients with stage 3 to 5 CKD without previous RRT and evaluated the association between outcomes and clinically relevant risk factors, including age and proteinuria. We also assessed whether CKD patients experienced ESRD or died before RRT, and compared the incidence of these outcomes after stratifying patients by CKD stage, age, and proteinuria level. Unlike previous studies on the prognosis of CKD patients, we followed up patients even after they started chronic RRT.     

Successful Treatment of Membranous Glomerulonephritis with Rituximab in Calcineurin Inhibitor-Dependent Patients

Background and objectives: Calcineurin inhibitors (CNIs) induce remission of proteinuria in most nephrotic patients with membranous glomerulonephropathy (MGN). However, 60% of patients become treatment dependent and are at risk of chronic nephrotoxicity. The aim of this study was to evaluate the efficacy of rituximab in patients with long-term dependence on CNIs.Design, setting, participants, and measurements: Thirteen patients with MGN, normal renal function, and proven dependence on CNIs, despite previous treatment with other immunosuppressant drugs, received a single trial of four weekly doses of rituximab (375 mg/m²). Outcome measures were the percentage of patients with CNI withdrawal and no evidence of relapse and the percentage of patients with complete or partial remission 30 mo after CNI withdrawal.Results: After rituximab, proteinuria decreased significantly (2.5 ± 0,76 basal versus 0.85 ± 0.17 at 6 mo; P = .0003). CNIs and other immunosuppressant drugs could be withdrawn in all patients with no evidence of relapse. After CNI withdrawal, GFR increased significantly (90.3 ± 15 basal to 106.4 ± 20 at 3 mo with a mean increase of 15.3% [range 0–20]). Three patients suffered a relapse of nephrotic proteinuria 19, 23, and 28 mo after rituximab treatment; all were successfully treated with a second course of rituximab. At 30 mo, all patients were in remission.Conclusions: In patients with MGN with long-term CNI dependence, rituximab can be an effective tool to overcome dependence on CNI, thus avoiding the risk of nephrotoxicity related to the chronic exposure to these drugs.Membranous glomerulonephropathy (MGN) is the most frequent cause of nephrotic syndrome in adults. There is general agreement that patients with persistent nephrotic syndrome are at risk of developing progressive renal insufficiency (1–4). In these patients, prospective randomized clinical trials have demonstrated that the calcineurin inhibitors (CNIs) cyclosporine (5,6) and tacrolimus (7) induce complete or partial remission of proteinuria in more than 70% of patients. However, more than 60% of patients treated with CNI suffer subsequent relapses or become treatment dependent (5–8) and need prolonged therapy to maintain remission, which exposes them to the nephrotoxic effects of this drugs. Consequently, for these patients, there is a need for the development of new treatment strategies aimed at reducing the risk of chronic nephrotoxicity. MGN is an antibody-mediated disease induced by deposits of immunoglobulins and complement components on the subepithelial layer of the glomerular capillary wall (9). This immune deposition promotes injury to the glomerular filtering barrier, proteinuria, and eventual renal failure (10). Infiltration of CD-20+ cells has also been demonstrated in renal biopsies of patients with MGN (11). Results in experimental MGN have shown that the inhibition of B cell function is associated with beneficial effects on proteinuria, (12) and human studies clearly demonstrated that the inhibition of B cells with alkylating agents induces remission of the nephrotic syndrome (13). The availability of monoclonal antibodies targeted to the cell surface antigen CD-20 of B cells permits an analysis of the effect of more selective and specific B cell inhibition in the outcome of several antibody-mediated diseases in clinical studies (14). In recent years, observational studies have shown that the administration of the anti-CD20 monoclonal antibody rituximab can reduce urinary protein excretion and preserve renal function in patients with MGN and persistent nephrotic syndrome (15–19).This pilot observational study was conducted in patients with MGN with normal renal function, who experienced long-term dependence on CNI despite previous treatment with high-dose immunoglobulins and mycophenolate mofetil. The study aim was to evaluate whether a single course of rituximab could allow either dose reduction or withdrawal of CNI.     

Renal Involvement in Primary Sj?gren's Syndrome: A Clinicopathologic Study

Background & objectives: Renal pathology and clinical outcomes in patients with primary Sjögren''s syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported.Design, setting, participants, & measurements: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted.Results: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment.Conclusions: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.Primary Sjögren''s syndrome (pSS) is a progressive autoimmune disorder involving the exocrine glands (1), typically presenting with keratoconjunctivitis and xerostomia (2). It is characterized pathologically by a predominant lymphocytic infiltrate around epithelial ducts of exocrine glands on salivary gland biopsy (3). Extraglandular manifestations of pSS, once thought to be uncommon, occur in up to 25% of patients. Patients can be afflicted by severe interstitial lung disease (4), cutaneous vasculitis (5), peripheral neuropathy (6), and hematologic complications such as lymphoma (7). They are also at increased risk for celiac sprue (8) and complications from Helicobacter pylori infection (9) such as mucosa-associated lymphatic tissue (MALT)-type lymphoma.Much of our understanding of the clinical presentation of renal involvement in pSS is based on case reports (10–26) and small retrospective cohorts (27–29). Tubulointerstitial nephritis (TIN) remains the most common presentation of renal involvement in pSS and CD4/CD8 T cell subsets are reported to predominate (27,30). This is often characterized by a distal (type I) renal tubular acidosis (RTA) and less commonly proximal (type II) RTA (Fanconi syndrome) (11,31–33). GN is thought to be a rare occurrence, with only case reports available in the literature (10,12–23), and tends to be a late development (34) in the course of the disease.We examined the renal pathologic findings and clinical trends of all patients with pSS who underwent kidney biopsy (KB) at Mayo Clinic since 1967 and assembled a case series of patients with pSS with renal pathologic disease evaluated by renal biopsy at a single center in the United States. This case series aimed to describe the common clinical presentations of renal disease in pSS, the array of pathologic findings of renal involvement in pSS, and trends during follow-up and treatment.     

Coronary Calcification in Patients with Chronic Kidney Disease and Coronary Artery Disease

Background and objectives: A close linkage between chronic kidney disease (CKD) and cardiovascular disease (CVD) has been demonstrated. Coronary artery calcification (CAC) is considered to be the causal link connecting them. The aim of the study is to determine the relationship between level of kidney function and the prevalence of CAC.Design, setting, participants, & measurements: Autopsy subjects known to have coronary artery disease and a wide range of kidney function were studied. Patients without CKD were classified into five groups depending on estimated GFR (eGFR) and proteinuria: eGFR ≥60 ml/min/1.73 m² without proteinuria; CKD1/2: eGFR ≥60 ml/min/1.73 m² with proteinuria; CKD3: 60 ml/min/1.73 m² >eGFR ≥30 ml/min/1.73 m²; CKD4/5: eGFR <30 ml/min/1.73 m²; and CKD5D: on hemodialysis. Intimal and medial calcification of the coronary arteries was evaluated. Risk factors for CVD and uremia were identified as relevant to CAC using logistic regression analysis.Results: Intimal calcification of plaques was present in all groups, but was most frequent and severe in the CKD5D group and less so in the CKD4/5 and CKD3 groups. Risk factors included luminal stenosis, age, smoking, diabetes, calcium-phosphorus product, inflammation, and kidney function. Medial calcification was seen in a small number of CKD4/5 and CKD5D groups. Risk factors were use of calcium-containing phosphate binders, hemodialysis treatment, and duration.Conclusions: It was concluded that CAC was present in the intimal plaque of both nonrenal and renal patients. Renal function and traditional risks were linked to initimal calcification. Medial calcification occurred only in CKD patients.Cardiovascular disease (CVD) is the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD) (1,2) or chronic kidney disease (CKD) (3–7). The mechanisms underlying this increased cardiovascular risk are not clearly understood. In the general population, traditional risk factors for CVD have been well characterized (8), and these are also present in CKD (3–6,9). The mechanisms involved in the connection between CKD and CVD are probably numerous (3–6). Vascular calcification, such as coronary artery calcification (CAC) (10,11), is considered to be the causal link between them.Vascular calcification is common in physiologic and pathologic conditions such as aging, diabetes, dyslipidemia, genetic diseases, and diseases with disturbances of calcium metabolism (12–14). In CKD patients, vascular calcification is even more common, developing early and contributing to the markedly increased cardiovascular risk. Pathomorphologically, atherosclerosis (plaque-forming degenerative changes of the aorta and of large elastic arteries) and arteriosclerosis (concentric medial thickening and hyalinosis of muscular arteries) can be distinguished. Increased knowledge about the mechanisms of calcification together with improved imaging techniques have provided evidence that vascular calcification should be divided into two distinct entities according to the specific site of calcification within the vascular wall: plaque calcification, involving patchy calcification of the intima in the vicinity of lipid or cholesterol deposits, and calcification of the media in the absence of such lipid or cholesterol deposits, known as Mönckeberg-type atherosclerosis (12–14). These two types of calcification may vary in terms of the type of vessel affected, the location along the arterial tree (proximal versus distal), clinical presentation, and treatment and prognosis (12–14). In the general population and in patients with CKD, electron-beam computed tomography (EBCT) has proven CAC as a potent predictor of cardiac events (15–18). Both the prevalence and intensity of CAC are increased in patients with CKD (19–27). Several studies have been undertaken to investigate whether calcification occurs in the intima or media of the coronaries and whether the morphologic details of calcified plaques differ between renal and nonrenal patients (12–14,24). Causal elements for either type of CAC have not been definitively determined (12–14).Autopsy studies are limited in terms of patient selection, but have a major advantage in terms of being able to distinguish intimal from medial calcification. Therefore, our primary goal is to determine whether, among autopsy subjects known to have CAD, there exists a direct relationship between level of kidney function and the prevalence of intimal or medial calcification.     

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.Design, setting, participants, and measurements: Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship.Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.Patients with diabetic kidney disease (DKD) are at increased risk for cardiovascular complications and early mortality. Those who survive long enough tend to progress to ESRD requiring dialysis or transplantation. Although advances in therapy with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor type II blockers (ARBs) have attenuated the incident rate of ESRD (1), disease progression remains common (2–4) and diabetes continues to be the leading cause for initiation of dialysis in the United States (1).Connective tissue growth factor (CTGF) is a 349-amino-acid secreted pleiotropic protein belonging to the cysteine-rich CCN (CTGF/Cyr61/Cef10/NOVH) family. Numerous glomerular, tubulointerstitial, and vascular cells types can produce CTGF, and many factors associated with the diabetic condition can stimulate CTGF expression, including hypertension, hyperglycemia, and hyperlipidemia (5–24).CTGF is a critical mediator of extracellular matrix accumulation and coordinates a final common pathway of fibrosis (5,25,26). CTGF has been shown to amplify the fibrogenic activity of TGFβ (27) and IGF-1 (17) and to inhibit the action of antifibrotic and regenerative factors bone morphogenic protein-7 (27,28) and vascular endothelial growth factor (29,30).In type 1 diabetes, plasma and urine CTGF levels correlate with the level of albuminuria and the stage of progressive renal insufficiency (31–34), and the plasma CTGF level is an independent predictor of vascular disease as assessed by intimal medial thickness (35) and of mortality and progression to ESRD (36). In renal biopsy specimens from patients with diabetes, elevated levels of CTGF mRNA are associated with chronic tubulointerstitial damage, albuminuria, and progression of renal insufficiency (37–39).FG-3019 is a recombinant human anti-CTGF monoclonal IgG₁ antibody that has shown activity in rodent models of kidney dysfunction associated with type 1 and 2 diabetes (40–42). Here, we report results of an open-label dose-escalation trial of FG-3019 infusions administered biweekly over 56 days in patients with DKD, the first study designed to evaluate safety and potential therapeutic effect of FG-3019 in this patient population.     

Outcomes Associated with Serum Calcium Level in Men with Non-Dialysis-Dependent Chronic Kidney Disease

Background and objectives: Elevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in non-dialysis-dependent (NDD) chronic kidney disease (CKD). Outcomes associated with low serum calcium are also not well-characterized.Design, setting, participants, & measurements: We examined associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in a historic prospective cohort of 1243 men with moderate and advanced NDD CKD by using Cox models.Results: The association of serum calcium with mortality varied according to the applied statistical models. Higher baseline calcium and time-averaged calcium were associated with higher mortality (multivariable adjusted hazard ratio (95% confidence interval): 1.31 (1.13, 1.53); P < 0.001 for a baseline calcium 1 mg/dl higher). However, in time-varying analyses, lower calcium levels were associated with increased mortality.Conclusions: Higher serum calcium is associated with increased long-term mortality (as reflected by the baseline and time-averaged models), and lower serum calcium is associated with increased short-term mortality (as reflected by the time-varying models) in patients with NDD CKD. Clinical trials are warranted to determine whether maintaining normal serum calcium can improve outcomes in these patients.Mineral and bone disorders in chronic kidney disease (CKD) (1) have emerged as novel mortality risk factors in dialysis patients (2–8). Some of these abnormalities (such as serum phosphorus and parathyroid hormone (PTH) levels) have also been implicated in similar ways in patients with non-dialysis-dependent (NDD) CKD (9–12). Serum calcium''s effect on outcomes has been the focus of attention mainly in dialysis patients, where calcium metabolism is significantly distorted (13–19). The use of calcium-containing phosphate binders further complicates the picture because these medications could be involved in the etiology of vascular calcification (20,21), and their roles as therapeutic agents have been intensely debated (22). Supporting the potential role for calcium in cardiovascular disease were epidemiologic studies showing an association between higher calcium and increased mortality (2–8). Some of the same studies have also suggested that extremely low calcium levels may themselves be deleterious (2,3), which has ultimately resulted in recommendations to attain a low-normal serum calcium level in dialysis patients (23). Studies examining the role of calcium in NDD CKD patients are fewer and failed to unequivocally show an association between abnormal calcium levels and vascular calcification (24–27). No study has yet examined the association of calcium levels with mortality in NDD CKD.We examined the association of serum calcium levels with all-cause mortality in a large number of male US veterans with moderate and advanced NDD CKD at a single medical institution.     

Hypophosphatemic Effect of Niacin in Patients without Renal Failure: A Randomized Trial

Background and objectives: Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease.Design, setting, participants, & measurements: We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268).Results: Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of −0.13 mmol/L (−0.15 to −0.13 mmol/L; −0.41 mg/dl [−0.46 to −0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or ≥60 ml/min per 1.73 m², a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus ≤1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use.Conclusions: We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to ≥90 ml/min per 1.73 m² (i.e., stages 1 through 3 chronic kidney disease).Abnormalities in calcium-phosphorus homeostasis, including significant elevations in serum phosphorus concentrations, are thought to contribute to arterial stiffening, hypertension, and cardiovascular disease (CVD) risk in patients with advanced chronic kidney disease and ESRD that requires maintenance dialysis (1–6). Observational data from population-based studies suggested that even serum phosphorus concentrations within the normative range are linearly associated with measures of subclinical arteriosclerosis and the development of incident CVD outcomes (7–12). Two cross-sectional studies from patients who underwent cardiac catheterization have further indicated that serum phosphorus concentrations, primarily within the normative range, were directly associated with both the presence and the severity of angiographic coronary artery disease (13,14). Moreover, a graded, independent association between serum phosphorus concentrations (again, within the normative range) and recurrent CVD events was reported among a large clinical trial cohort of patients with a previous myocardial infarction (15).Supplementation of calcium salts, despite their efficacy and tolerability as a phosphorus-lowering treatment in ESRD, may enhance coronary artery and aortic valve calcification (16,17). This observation highlights the need for hyperphosphatemia treatment protocols to balance potential benefits and adverse effects (18–22). Phosphorus-lowering drugs that target other cardiovascular risk factors in chronic kidney disease (CKD), simultaneously, including, for example, dyslipidemia (23), might have additive or synergistic benefits. These findings may also be relevant to populations with less advanced CKD or normal renal function.Preliminary studies suggested that niacin administration (as niacinamide, niceritrol, or nicotinic acid) could be a useful primary or adjunctive treatment for the marked hyperphosphatemia that is characteristic of ESRD (24–30). Several reports from clinical trials of extended-release niacin (ERN) that was given to patients who had dyslipidemia and were free of clinical renal disease and hyperphosphatemia have contained limited additional data noting up to 10% reductions in the serum phosphorus concentrations of actively treated patients (31–34). These repeated clinical observations (24–34) are most plausibly explained by the direct inhibitory effect of niacin compounds on active transport-mediated phosphorus absorption in the mammalian small intestine (35–39).Published studies of patient populations who had dyslipidemia and were receiving ERN that included phosphorus data may have failed to provide information on baseline phosphorus values (33,34), and none (31–34) performed repeated measures analyses to examine the potential effects of niacin treatment on serum phosphorus and calcium concentrations, as well as the calcium-phosphorus products.Focused reexamination of the large, placebo-controlled clinical trial data set assembled by Maccubbin et al. (34) afforded us a unique opportunity to elucidate these and other unresolved issues regarding the impact of niacin given as the fixed-dose combination of ERN and laropiprant (ERN-L), a selective prostaglandin D2 receptor subtype 1 inhibitor that reduces niacin-induced flushing (34) or ERN alone on serum phosphorus and calcium concentrations and calcium-phosphorus products. We further evaluated whether there was evidence for significant effect modification by estimated GFR (eGFR), baseline serum phosphorus concentration, the presence of diabetes, or concurrent hepatic hydroxymethyl glutaryl–CoA reductase inhibitor (statin) use when assessing the potential impact of niacin on these routine clinical measures of calcium-phosphorus homeostasis.     

Rituximab Treatment of Adult Patients with Steroid-Resistant Focal Segmental Glomerulosclerosis

Background and objectives: Isolated case reports have shown a beneficial effect of rituximab on pediatric patients with primary FSGS, but there is no information about rituximab treatment of FSGS in adults.Design, setting, participants, & measurements: All patients who had biopsy-proven FSGS and were treated with rituximab in Spain were identified, independent of their positive or negative response, among the nephrology departments that belong to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Their characteristics and outcome after rituximab treatment were studied.Results: Eight patients were identified. Rituximab failed to improve nephrotic syndrome in five of eight patients, who continued to show massive proteinuria and exhibited a rapidly deteriorating renal function in two cases. Among the remaining three patients, two of them showed an improvement of renal function and a remarkable proteinuria reduction and one experienced a beneficial but transitory effect after rituximab. There were no differences in clinical or laboratory characteristics or in the CD20 B lymphocyte count after rituximab between these three patients and the five who had a negative response. The only difference was in the regimen of rituximab administration: Whereas the five patients with a negative response received only four weekly consecutive infusions of 375 mg/m², the three remaining patients received additional doses of rituximab.Conclusions: Only a minority (three of eight) of patients in our series of adult patients with FSGS showed a positive influence of rituximab. More studies are necessary to characterize further the optimal dosages and the mechanisms of action of rituximab in FSGS.The treatment of idiopathic steroid-resistant FSGS remains a worrying challenge for nephrologists. Cyclosporine has demonstrated a beneficial effect in some prospective, randomized studies, inducing partial or complete remission in a majority of treated patients (1); however, relapses are common after cyclosporine withdrawal, and the risk for chronic nephrotoxicity when the drug is maintained for long periods remains an important concern. Some observational studies have suggested a beneficial effect of tacrolimus, mycophenolate, sirolimus, ACTH, or plasmapheresis on some patients, but prospective, controlled studies are lacking.Rituximab is a mAb directed against the cell surface antigen CD20 of B lymphocytes. It is an effective therapy for non-Hodgkin''s lymphoma and other B cell malignancies (2). Several reports of successful use of rituximab in systemic diseases and immune-mediated renal disorders have been published, including membranous glomerulonephritis, lupus nephritis, vasculitis, mixed cryoglobulinemia, and thrombotic thrombocytopenic purpura (3,4).Some case reports have suggested that rituximab could be effective to resolve recurrent nephrotic syndrome after renal transplantation in patients whose primary renal disease was FSGS (5–9). The potential usefulness of rituximab has also been explored in patients with steroid-dependent or steroid-resistant forms of nephrotic syndrome. Several case reports and observational studies strongly suggest that rituximab could be an effective treatment for steroid-dependent nephrotic syndrome because the great majority of treated patients (most of them children) have experienced long-lasting periods of remission without steroids or other immunosuppressive drugs (10–12). Nevertheless, no prospective, randomized trials have been performed to compare the efficacy of this treatment with other available therapies for steroid-dependent nephrotic syndrome. Regarding steroid-resistant nephrotic syndrome, a few case reports of children with biopsy-proven FSGS and one adult with minimal-change disease in whom rituximab induced a complete or partial remission of nephrotic syndrome have been reported (13–16). As far as we know, no studies about rituximab treatment of adult patients with steroid-resistant nephrotic syndrome as a result of FSGS in their native kidneys have been published. Moreover, in the absence of prospective, controlled trials, anecdotal case reports tend to publish preferably patients with a positive response to innovative treatments. For all of these reasons, we collected the experience with rituximab-treated patients with FSGS among the nephrology departments that belong to the Spanish Group for the study of Glomerular Diseases (GLOSEN).     

Obesity-Related Glomerulopathy: Body Mass Index and Proteinuria

Background and objectives: Obesity-related glomerulopathy (ORG) is an increasing cause of end-stage renal disease, but evidence concerning the effects of treatments is rather limited. This study was aimed at exploring the renoprotective effects of weight loss on patients with ORG.Design, setting, participants, & measurements: A total of 63 patients with renal biopsy–proven ORG had food and exercise intervention in the physician-supervised weight loss program and were divided into three groups on the basis of the percentage of weight change from baseline to follow-up: significant weight loss (>3% reduction in body mass index [BMI]), stable weight, or significant weight gain (>3% increase). Metabolic parameters and renal lesions were evaluated regularly for 2 years.Results: After 6 months, 27 patients lost weight by 8.29 ± 4.00%, with a mean decrease in proteinuria of 35.3%, whereas 24 months later, 27 patients achieved a 9.20 ± 3.78% reduction in BMI and a 51.33% reduction in urine protein secretion. The levels of serum triglyceride, serum uric acid, and BP were also decreased. Contrarily, in patients with increased BMI, urine protein was increased by 28.78%. Correlation analysis showed proteinuria was associated with BMI, serum triglyceride, and uric acid, and multivariate regression analysis indicated the changes in BMI were the only predictor of proteinuria (P < 0.01).Conclusions: Weight loss intervention benefited remission of proteinuria in patients with ORG, whose function could not be replaced by conventional pharmacotherapy.Profound lifestyle changes in modern China have resulted in a remarkable increase in the population of obesity (1). Sequelae of obesity include type 2 diabetes, hypertension, cardiovascular diseases, and the progression of renal diseases (2,3). Weight loss, either after bariatric surgery or after lifestyle modification, normalizes blood glucose (4) and decreases BP and plasma lipids (5,6) in obese patients. Similarly, a significant reduction in urinary albumin excretion and glomerular hyperfiltration has been reported in morbidly obese patients with a dramatic decrease of body mass index (BMI) (7,8). Moreover, even a small decrease in BMI is related to the reduction of proteinuria in patients with diabetic nephropathy and other chronic kidney diseases (9–11).Obesity-related glomerulopathy (ORG) has been reported in more and more obese patients without overt diabetes and pre-existing renal diseases (12,13). It is a secondary form of focal and segmental glomerulosclerosis (FSGS) manifested as proteinuria and progressive renal dysfunction (14). The prognosis for patients with ORG were significantly different from those with diabetic nephropathy or with the primary form of FSGS (15). However, the relationship between weight loss and the outcome of ORG has not been clarified until now. Conclusions from the studies of diabetic nephropathy (9) and unidentified chronic kidney diseases (10,11,16) could be different from those of histologic-proven ORG. And evidence from case reports (17,18) concerning the aggressive treatment of ORG with bariatric surgery is unpersuasive because only a small population was involved. In addition, the long-term effects of weight loss in patients with ORG are not studied. So far, no well-designed clinical research studies for histologic-proven ORG are available, especially those concerning the long-term effects of weight loss and lifestyle modification.In this regard, this study was designed to observe the relationship between body weight reduction and the changes in proteinuria in patients with ORG. Patients who were diagnosed with ORG by renal biopsy were included in the physician-supervised weight loss program in our institute and followed up for 2 years. It was the first study demonstrating that the remission of ORG could be achieved in patients with weight loss, but not in patients with increasing body weight.     

Phosphoinositides and SNARE chaperones synergistically assemble and remodel SNARE complexes for membrane fusion

Yeast vacuole fusion requires 4 SNAREs, 2 SNARE chaperone systems (Sec17p/Sec18p/ATP and the HOPS complex), and 2 phosphoinositides, phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. By reconstituting proteoliposomal fusion with purified components, we now show that phosphoinositides have 4 distinct roles: PI(3)P is recognized by the PX domain of the SNARE Vam7p; PI(3)P enhances the capacity of membrane-bound SNAREs to drive fusion in the absence of SNARE chaperones; either PI(3)P or PI(4,5)P₂ can activate SNARE chaperones for the recruitment of Vam7p into fusion-competent SNARE complexes; and either PI(3)P or PI(4,5)P₂ strikingly promotes synergistic SNARE complex remodeling by Sec17p/Sec18p/ATP and HOPS. This ternary synergy of phosphoinositides and 2 SNARE chaperone systems is required for rapid fusion.Intracellular membrane fusion is a conserved reaction, vital for vesicle trafficking, hormone secretion, and neurotransmission. Fusion is regulated by NSF (N-ethylmaleimide-sensitive factor)/Sec18p, αSNAP (soluble NSF attachment protein)/Sec17p, SNAREs (SNAP receptors), Sec1p/Munc18–1p family (SM) proteins, Rab GTPases, and Rab:GTP-binding proteins, termed “Rab effectors” (1–3). Lipids, including phosphoinositides, sterols, diacylglycerol (DAG), and phosphatidic acid (PA), have specific roles in fusion (4–14). Proteins and lipids cooperate for their enrichment in membrane fusion microdomains (6, 8, 15, 16).SNARE proteins are integral or peripheral membrane proteins required for membrane fusion. SNAREs have either a Q or R residue at the center of their SNARE domain and associate in 4-helical QabcR complexes in cis (anchored to one membrane) or in trans (anchored to apposed membranes), where a, b, and c are families of related Q-SNAREs (2, 17, 18). Reconstituted proteoliposomes (RPLs) bearing Q-SNAREs fuse with RPLs bearing an R-SNARE through trans-SNARE-complex assembly (19, 20). This fusion has slow kinetics, requires nonphysiologically high SNARE densities, and causes substantial leakage of luminal contents of the RPLs (21–24).We study membrane fusion with yeast vacuoles (lysosomes). Vacuole fusion (25) requires 3 Q-SNAREs (Vam3p, Vti1p, and Vam7p) and 1R-SNARE (Nyv1p) (26, 27), two SNARE chaperone systems, Sec17p/Sec18p/ATP (28), and the HOPS (homotypic fusion and vacuole protein sorting)/Vps Class C complex (29, 30), the Rab-GTPase Ypt7p (31), and chemically minor but functionally vital “regulatory lipids”: ergosterol (ERG), DAG, PI(3)P, and PI(4,5)P₂ (8). Inactive 4SNARE cis-complexes on isolated organelles are disassembled by Sec17p/Sec18p/ATP (27). The heterohexameric HOPS complex, containing the SM protein Vps33p as a subunit, promotes and proofreads SNARE-complex assembly (32–34). HOPS can physically interact with the Q-SNAREs [Vam7p (35) and Vam3p (36, 37)], 4SNARE cis-complexes (32), GTP-bound Ypt7p (29), and phosphoinositides (35). PI(3)P supports the membrane association of the Qc-SNARE Vam7p, which has no transmembrane domain, through binding its PX domain (38). SNAREs, HOPS, Ypt7p, and regulatory lipids assemble in an interdependent fashion to form a fusion-competent membrane microdomain, the “vertex ring” (8, 16, 39). Trans-SNARE complexes are essential for fusion (26), yet fusion can be accelerated by SNARE-associating factors such as HOPS (14, 35) and by cycles of SNARE complex disassembly and reassembly, termed “remodeling” (40).Membrane fusion has been reconstituted with all purified yeast vacuolar components, including 4SNAREs, vacuolar lipids, 2 SNARE chaperone systems, and phosphoinositides (14). We now show distinct functions of phosphoinositides in RPL fusion: the PX-domain of the SNARE Vam7p recognizes PI(3)P, as reported (38); PI(3)P activates the 3Q-SNAREs to be more fusogenic in the absence of SNARE chaperones; either PI(3)P or PI(4,5)P₂ accelerates fusion by promoting the synergy between Sec17p/Sec18p and HOPS, although this synergy is not a function of the membrane recruitments of these SNARE chaperones. This ternary synergy between phosphoinositides and SNARE chaperones is essential for the assembly and remodeling of SNARE complexes.     

A state-mutating genetic algorithm to design ion-channel models

Realistic computational models of single neurons require component ion channels that reproduce experimental findings. Here, a topology-mutating genetic algorithm that searches for the best state diagram and transition-rate parameters to model macroscopic ion-channel behavior is described. Important features of the algorithm include a topology-altering strategy, automatic satisfaction of equilibrium constraints (microscopic reversibility), and multiple-protocol fitting using sequential goal programming rather than explicit weighting. Application of this genetic algorithm to design a sodium-channel model exhibiting both fast and prolonged inactivation yields a six-state model that produces realistic activity-dependent attenuation of action-potential backpropagation in current-clamp simulations of a CA1 pyramidal neuron.The importance of modeling ion channels has been understood since Hodgkin and Huxley''s seminal work with the squid giant axon (1). Subsequently, the development of the patch-clamp method (2) enabled the characterization of the properties of a wide range of channels, and intensive efforts followed to produce quantitative models that could predict and explain specific ion-channel behavior (3–7). Such efforts have led to two broad classes of models: those describing single-channel and gating currents, and those describing macroscopic currents.Models of single-channel and gating currents can be used to analyze properties such as open-channel probabilities, dwell times, and activation kinetics; they therefore facilitate an improved understanding of channel biophysics (3–5, 7–9). By contrast, models of macroscopic currents are usually intended as empirical tools as part of larger compartmental models of neurons. Such a macroscopic model may not necessarily describe the actual molecular state changes of the channel; the goal is rather for it to function as a “black-box” that reproduces the mean behavior of a population of channels. Hodgkin and Huxley''s (1) original formulation of sodium- and potassium-channel models is a prime example of this case, and its basic formalism continues to be widely used to generate empirical ion-channel models.An alternative to the Hodgkin–Huxley formalism is the state-dependent modeling approach (3). In reality, state-dependent models subsume Hodgkin–Huxley models because the latter can be recast as the former (3). State-dependent models are more general, however, because they can describe certain behaviors more easily than Hodgkin–Huxley type models, such as having widely different transition rates into and out of a given state (10). In general, the gold standard for the use of state-dependent models is single-channel recording (3, 5, 11), but the state-dependent formalism is also often employed in models of macroscopic currents (12–15) because of the generality and flexibility it affords.Methods to make empirical state-dependent models conform to data have been studied extensively and have involved a multitude of techniques such as hand fitting (12–14, 16), principal-axis fitting (17), maximum-likelihood estimation (5, 7, 17, 18), and genetic algorithms (15), among others. Here, we present a new fitting technique based on a topology-mutating genetic algorithm. Genetic algorithms have a number of useful characteristics: First, they have been shown to explore a large area of parameter space with relatively quick convergence, especially for problems with many parameters (19). Second, they are easily parallelizable. Third, they have been successfully applied to neuronal modeling, both for Hodgkin–Huxley-type ion-channel parameters and for compartmental neuronal models with voltage-activated conductances (15). Here we show that if the ion-channel model is formulated properly, genetic algorithms provide a natural way to incorporate changes in model topology as mutations.The algorithm presented here has several key features. Most notably, whereas other published optimization algorithms fix the model topology and optimize the rate constants, our algorithm searches over the space of model topologies and the space of rate parameters simultaneously. In order to design such an algorithm appropriate for state-dependent ion-channel models, we formulated an automated, computationally efficient method to satisfy the principle of microscopic reversibility, an equilibrium condition that imposes constraints on topologies with loops (20, 21). Finally, our algorithm uses a sequential approach, also known as goal programming (22), to optimize multiple protocols without the need to assign weights to each of the objective functions. The ability of this genetic algorithm to select and examine topologies not previously explored demonstrates its flexibility in developing working empirical models.We applied this genetic algorithm to devise a sodium-channel model that exhibits both fast and slow inactivation. Fast inactivation refers to a nonconducting channel state that follows quickly after depolarization and activation (within milliseconds) and from which channels recover quickly when the voltage is restored to resting levels (1). In response to either sustained depolarization (23, 24) or a train of depolarizing pulses (16, 25), however, the fraction of sodium channels available for activation also decreases rapidly, but in this case recovery occurs much more slowly, on the order of seconds rather than milliseconds. This form of inactivation has therefore been called “prolonged” or “slow” (16, 25). The presence of such widely disparate time scales makes the creation of state-dependent models of these channels a challenge. At the same time, the effect of prolonged inactivation on processes such as action-potential backpropagation (26, 27), transitions from bursting to spiking (28), and dendritic spiking (29, 30) makes the development of accurate models of prolonged inactivation important for computational simulations of neuronal function.     

Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin System Blockade: The ESPLANADE Trial

Background and objectives: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade.Design, setting, participants, & measurements: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat.Results: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated.Conclusions: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.Individuals with chronic kidney disease (CKD) have substantially higher mortality rates compared with those in the general population (1). The increased risk is multifactorial in origin, but is largely due to accelerated atherosclerosis, which in turn is driven by high prevalence of traditional cardiovascular risk factors in renal populations. The presence of proteinuria is associated with more rapid kidney function loss (2), and also increases the risks of cardiovascular morbidity and mortality (3). Dyslipidemia is a complication of both decreased kidney function and proteinuria (4) and could accelerate progression of renal disease by several mechanisms. First, tubular epithelial cells reabsorb fatty acid and cholesterol from filtered albumin and lipoproteins, which can stimulate tubulointerstitial inflammation and tissue injury (5). Second, lipoproteins may accumulate in glomerular mesangium, promoting excess matrix production and glomerulosclerosis (6).Inhibitors of the renin-angiotensin system (RAS) such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) reduce proteinuria by mechanisms largely independent of BP control (7), an effect that is enhanced when they are used in combination (8–10) and is associated with significant renoprotection (10–12). They may also ameliorate the dyslipidemia associated with CKD by different mechanisms including amelioration of the nephrotic syndrome and of endothelial dysfunction, an effect that fully manifests at doses higher than those required to reduce the BP (13). Whether this effect is enhanced when they are used in combination is unknown.In animals, 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors or statins, in addition to reducing LDL cholesterol, decrease proteinuria and preserve renal function and structure (14), especially when used together with ACEi and/or ARB (15). These renoprotective effects appear to be mediated, at least in part, by the limitation of inflammatory and oxidative stress, endoplasmic reticulum stress, endothelial dysfunction, and RAS activation achieved by cholesterol reduction (reviewed in reference 16). However, inhibited production of nonsteroidal compounds such as farnesyl pyrophosphate and geranyl-geranyl-pyrophosphate involved in subcellular localization and intracellular trafficking of membrane-bound proteins mediating oxidative stress injury such as Rho, Ras, and Rac GTPases may also contribute to decrease in monocyte/macrophage glomerular infiltration, mesangial proliferation, extracellular matrix accumulation, and fibrosis. Endothelin 1 inhibition and upregulation of endothelial nitric synthase expression may also play a role (16).The above mechanisms might also explain some of the effects observed in humans. Subgroup analyses of 15 trials primarily aimed at evaluating the effect of statins on serum lipids in patients at increased cardiovascular risk found that statin therapy significantly decreased proteinuria in those patients who had predialysis CKD at inclusion (17). The antiproteinuric effect was greater among patients with more proteinuria (18). Consistent with experimental data, two randomized clinical trials found that statin therapy decreased proteinuria and ameliorated dyslipidemia more effectively than placebo also in CKD patients on ACEi or ARB therapy (19,20). However, failure of a recent meta-analysis to detect a significant treatment effect on creatinine clearance decline cannot be taken to definitely exclude the possibility of specific renoprotective properties of statins because results were flawed by the unreliability of creatinine clearance to reflect true GFR changes over time, too short follow-up, and significant heterogeneity of considered trials (21). Independent of the above, whether statins limit proteinuria and dyslipidemia also in people who are already receiving combination therapy with ACEi and ARB is unknown.Thus, in the European Study for Preventing by Lipid-lowering Agents aNd ACE-inhibition Dialysis Endpoints (ESPLANADE), we addressed whether and to what extent the proteinuria and dyslipidemia of CKD are ameliorated by add-on statin therapy in hypertensive patients with CKD and residual proteinuria despite combined ACEi and ARB therapy.     

Training of Surgeons in Peritoneal Dialysis Catheter Placement in the United States: A National Survey

Background and objectives: Peritoneal dialysis (PD) depends on timely and skilled placement of a PD catheter (PDC). Most PDCs are placed surgically, but little is known about the residency training of surgeons in this procedure. Inadequate residency training could limit surgical expertise in PDCs, resulting in high complication rates that discourage PD use. This study assessed surgical PDC training in the United States to explore this issue.Design, setting, participants, & measurements: A survey was sent to program directors of 248 U.S. surgery residency programs regarding the amount of PDC training, attitudes toward PDCs, and barriers to PDC training. Results were compared between academic and private centers.Results: Ninety-three surgery programs (38%) responded: 82% provided training in PDC and 69% were academic centers. Most surgeons placed 2 to ≤5 catheters during residency. Forty-eight percent of program directors felt that PDC training was important, 61% felt PDC training affected outcomes and increased the likelihood surgeons would place PDCs in practice, and 62% of programs expressed willingness to provide more PDC training. Lack of referrals from nephrology was the most frequently cited barrier to PDC training.Conclusions: Although many U.S. surgery residency programs provide PDC training, this training appears inadequate. Low PD use and lack of referrals limits surgical training at most centers. Nephrologists need to develop initiatives with surgeons to improve PDC training and outcomes.The use of peritoneal dialysis (PD) in the United States is declining. Despite comparable efficacy, improving outcomes, and cost savings compared with hemodialysis (HD), only 6% of incident and 7.2% of prevalent dialysis patients are treated with PD (1–4). Although many factors determine success on PD, a well functioning PD catheter (PDC) is absolutely necessary. Placement of a PDC by an experienced operator is strongly recommended to reduce complications (5–9). Little attention has been given to the potential effect of surgical PDC training on PD use and outcomes (1–2,10). Conversely, considerable focus has been placed on improving surgical training and outcomes for HD access (11–15).Problems with PDC placement and malfunction can disrupt efforts to grow and develop a PD program (5,9,16–18). PDC problems frustrate patients, nurses, and nephrologists alike, leading to dissatisfaction with PD and an early switch to HD (18). PDC malfunction is second only to infection as the cause of technique failure in PD (19,20). Surgeons insert most PD catheters in the United States because most nephrologists are not trained in PDC placement (5,21–23). Unfortunately, there is a shortage of surgeons interested and skilled in performing this procedure (5).Surgical outcomes correlate strongly with training during residency (24). Reluctance by surgeons to place PDCs and suboptimal PDC outcomes might stem from inadequate residency training. Unfortunately, little is known about the training surgeons undergo in this outwardly simple, yet critical procedure. We sought to investigate PDC training in U.S. surgery residency programs and explore surgical program directors'' attitudes toward this procedure.     

Robustness of topological order and formation of quantum well states in topological insulators exposed to ambient environment

The physical property investigation (like transport measurements) and ultimate application of the topological insulators usually involve surfaces that are exposed to ambient environment (1 atm and room temperature). One critical issue is how the topological surface state will behave under such ambient conditions. We report high resolution angle-resolved photoemission measurements to directly probe the surface state of the prototypical topological insulators, Bi₂Se₃ and Bi₂Te₃, upon exposing to various environments. We find that the topological order is robust even when the surface is exposed to air at room temperature. However, the surface state is strongly modified after such an exposure. Particularly, we have observed the formation of two-dimensional quantum well states near the exposed surface of the topological insulators. These findings provide key information in understanding the surface properties of the topological insulators under ambient environment and in engineering the topological surface state for applications.The topological insulators represent a novel state of matter where the bulk is insulating but the surface is metallic, which is expected to be robust due to topological protection (1–5). The topological surface state exhibits unique electronic structure and spin texture that provide a venue not only to explore novel quantum phenomena in fundamental physics (6–10) but also to show potential applications in spintronics and quantum computing (2,5,11). The angle-resolved photoemission spectroscopy (ARPES) is a powerful experimental tool to directly identify and characterize topological insulators (12). A number of three-dimensional topological insulators have been theoretically predicted and experimentally identified by ARPES (13–21); some of their peculiar properties have been revealed by scanning tunneling microscopy (STM) (22–26). The application of the topological surface states depends on the surface engineering that can be manipulated by incorporation of nonmagnetic (27–31) or magnetic (27, 28, 31–33) impurities or gas adsorptions (27, 33–35). While the ARPES and STM measurements usually involve the fresh surface obtained by cleaving samples in situ under ultrahigh vacuum, for the transport and optical techniques, which are widely used to investigate the intrinsic quantum behaviors of the topological surface state (36–40), and particularly the ultimate applications of the topological insulators, the surface is usually exposed to ambient conditions (1 atm air and room temperature) or some gas protection environment. It is therefore crucial to investigate whether the topological order can survive under the ambient conditions and, furthermore, whether and how the surface state may be modified after such exposures.     

Prevalence and Prognostic Significance of Renal Artery Calcification in Patients with Diabetes and Proteinuria

Background and objectives: Vascular calcification is common and severe in chronic kidney disease. Because the consequences of calcification may differ by vascular beds, we sought to test the hypothesis that patients who have diabetes with proteinuria and have significant renal artery calcification (RAC) have a higher risk for progression to ESRD.Design, setting, participants, & measurements: Using electron-beam computed tomography, RAC was computed as the sum of Agatston scores at each of the two renal ostia and renal arteries. Time-to-event analysis was conducted to compare the risk in individuals with or without significant RAC (total score >10).Results: Of 172 patients with type 2 diabetes and overt proteinuria studied (estimated GFR 56 ± 25 ml/min per 1.73 m²), significant RAC was present in 31%. In 33 ± 21 months, 41 progressed to ESRD and 65 reached a composite outcome (ESRD or death). Serum phosphorus was a significant predictor of progression to ESRD but was replaced by the significant RAC in multivariate models that included the latter. Individuals with significant RAC had a higher risk for reaching the composite outcome. In contrast, there was no association between coronary artery calcification scores and progression to ESRD.Conclusions: Significant RAC was an independent predictor of progression to ESRD as well as reaching the composite outcome. Understanding the pathogenesis of RAC would allow determination of whether this risk is potentially modifiable.Advancing chronic kidney disease (CKD) is characterized by a progressive inability to excrete phosphorus and is associated with worsening abnormalities in mineral metabolism. Changes such as an increase in serum parathyroid hormone and fibroblast growth factor 23 begin early during the course of CKD and serve to maintain serum phosphorus within the reference range in most patients until late in the course of the disease (1–3). In addition to inducing renal osteodystrophy, higher serum phosphorus levels within the reference range are associated with higher risk for all-cause mortality in individuals with and without CKD (4,5). Furthermore, epidemiologic studies of patients with CKD have shown a graded relationship between serum phosphorus levels and rate of loss of GFR or progression to ESRD (6–8). The biological basis of this association in humans has not been well studied; however, CKD is associated with intrarenal calcification in animal models, which is ameliorated with dietary phosphorus restriction (9–12). Furthermore, vascular calcification is an active cell-mediated process, and phosphorus has been shown to be an important mediator for the induction and progression of vascular calcification in cell culture and animal studies (13,14), so it seems reasonable to postulate that extraskeletal calcification may be a biological basis for the association that is seen between serum phosphorus and progression of CKD.Vascular calcification begins early and is often severe early during the course of CKD, particularly among those with diabetes. Most of the studies in CKD have focused on either coronary or peripheral arterial calcification. The prognostic value of coronary artery calcification (CAC) has been established in many populations—our group has extended these findings to patients with diabetes and proteinuria (15)—however, calcification occurs in many vascular beds, including the renal arteries (16–20). The clinical relevance of renal artery calcification (RAC) has heretofore not been studied. We undertook this study to test the hypothesis that among patients with diabetes and proteinuria, the presence of significant RAC is associated with a higher risk for progression to ESRD and a composite outcome of either progression to ESRD or all-cause mortality.     

Prevalence of Atrial Fibrillation and Its Predictors in Nondialysis Patients with Chronic Kidney Disease

Background and objectives: Chronic kidney disease (CKD) increases systemic inflammation, which is implicated in development and maintenance of atrial fibrillation (AF); therefore, we hypothesized that the prevalence of AF would be increased among nondialysis patients with CKD. This study also reports independent predictors of the presence of AF in this population.Design, setting, participants, & measurements: A retrospective, cross-sectional analysis of 1010 consecutive nondialysis patients with CKD from two community-based hospitals was conducted. Estimated GFRs (eGFRs) were calculated using the Modification of Diet in Renal Disease (MDRD) equation. Multivariate logistic regression was used to determine independent predictors.Results: Of 1010 nondialysis patients with CKD, 214 (21.2%) had AF. Patients with AF were older than patients without AF (76 ± 11 versus 63 ± 15 yr). The prevalence of AF among white patients (42.7%) was higher than among black patients (12.7%) or other races (5.7%). In multivariate analyses, age, white race, increasing left atrial diameter, lower systolic BP, and congestive heart failure were identified as independent predictors of the presence of AF. Although serum high-sensitivity C-reactive protein levels were elevated in our population (5.2 ± 7.4 mg/L), levels did not correlate with the presence of AF or with eGFR. Finally, eGFR did not correlate with the presence of AF in our population.Conclusions: The prevalence of AF was increased in our population, and independent predictors were age, white race, increasing left atrial diameter, lower systolic BP, and congestive heart failure.Atrial fibrillation (AF) is the most common arrhythmia in clinical practice (1). Cardiac comorbidities that are associated with AF include hypertension, coronary artery disease (CAD), valvular heart disease (VHD), congestive heart failure (CHF), cardiomyopathy, pericarditis, congenital heart disease (CHD), and cardiac surgery (2–9). Noncardiac comorbidities that are associated with AF include acute pulmonary embolism, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, hyperthyroidism, and obesity (10–14).Evidence suggests that inflammation is involved in the pathogenesis of AF (15–20). For example, AF after cardiac surgery is associated with proinflammatory cytokine and complement activation (16,19). Moreover, patients with refractory lone AF have inflammatory infiltrates, myocyte necrosis, and fibrosis on biopsy (18). Several studies also reported elevated serum high-sensitivity C-reactive protein (hsCRP) levels in patients with AF (15–17,20).Evidence suggests that inflammation is associated with renal dysfunction (21–24). Proposed mechanisms include decreased proinflammatory cytokine clearance, endotoxemia, oxidative stress, and reduced antioxidant levels (23,24). Moreover, hsCRP levels are higher among elderly patients with renal insufficiency (24). In hemodialysis (HD) patients with ESRD, hsCRP, IL-6, and fibrinogen levels are elevated (21,22).HD patients with ESRD have an increased prevalence of AF; however, prevalence among nondialysis patients with CKD has not been investigated (25–30). Because CKD promotes inflammation, which promotes AF, we hypothesized the prevalence of AF would be increased among nondialysis patients with CKD. This study reports the prevalence and independent predictors of the presence of AF in a nondialysis population with CKD.     

Recent assembly of the Cerrado,a neotropical plant diversity hotspot,by in situ evolution of adaptations to fire

The relative importance of local ecological and larger-scale historical processes in causing differences in species richness across the globe remains keenly debated. To gain insight into these questions, we investigated the assembly of plant diversity in the Cerrado in South America, the world''s most species-rich tropical savanna. Time-calibrated phylogenies suggest that Cerrado lineages started to diversify less than 10 Mya, with most lineages diversifying at 4 Mya or less, coinciding with the rise to dominance of flammable C4 grasses and expansion of the savanna biome worldwide. These plant phylogenies show that Cerrado lineages are strongly associated with adaptations to fire and have sister groups in largely fire-free nearby wet forest, seasonally dry forest, subtropical grassland, or wetland vegetation. These findings imply that the Cerrado formed in situ via recent and frequent adaptive shifts to resist fire, rather than via dispersal of lineages already adapted to fire. The location of the Cerrado surrounded by a diverse array of species-rich biomes, and the apparently modest adaptive barrier posed by fire, are likely to have contributed to its striking species richness. These findings add to growing evidence that the origins and historical assembly of species-rich biomes have been idiosyncratic, driven in large part by unique features of regional- and continental-scale geohistory and that different historical processes can lead to similar levels of modern species richness.The uneven distribution of species diversity across the globe and the occurrence of biodiversity hotspots with high concentrations of species are well established (1–3). However, the underlying causes of differences in species diversity and composition among biomes and the processes that have prompted accumulation of high species diversity in some areas remain poorly understood (4–6). Correlations between species richness and annual energy input, water supply, and physiographic complexity suggest that climatic and other environmental factors are major determinants of species diversity (7). Indeed, it has been shown that these factors can accurately predict the locations of most global diversity hotspots and account for the latitudinal gradient of species richness (7). However, such insights contribute little to our understanding of the historical assembly of species-rich biomes and the larger-scale evolutionary processes that have generated global patterns of diversity (4, 8, 9). Little is known about the historical and geographical assembly of species-rich biomes (5), in terms of when, how quickly, and from where the species and lineages that make up different biomes have been recruited and how they subsequently evolved in situ. This lack of data on geographical and temporal patterns of species diversification, especially in the tropics where most diversity resides, makes it difficult to assess why there are so many species in these areas, to what extent variation in diversity can be attributed to regional and continental-scale historical contingencies (4, 10, 11), and to compare patterns among different species-rich biomes (9, 12).Recent discussion has highlighted the potential role of phylogenetic niche conservatism in shaping regional species pools (8, 13) and explaining diversity gradients (11). Prominent examples of large-scale niche or biome conservatism have been documented for the tropical–temperate biotas (11), mangroves (14), southern hemisphere extratropical biomes (13), Andean grasslands (8, 15), and seasonally dry tropical forests (16–18). However, the extent to which this tendency to retain ancestral ecology across lineages has influenced species composition in the most species-rich tropical biomes is unknown.Recent insights into the historical assembly of species diversity and biomes have come from time-calibrated phylogenies for biome-specific lineages (5, 9, 19–23). Phylogenies have potential for reconstructing transitions from precursor to modern biotas and identifying the underlying factors that drive these processes (4, 11, 24). However, the sparse sampling of lineages and species in such studies (5, 24) has limited these insights to a few well-studied areas such as the Cape Floristic Region (12, 20).     

Interferon for Hepatitis C Virus in Hemodialysis—an Individual Patient Meta-analysis of Factors Associated with Sustained Virological Response

Background and objectives: Hepatitis C virus (HCV) infection is prevalent in hemodialysis patients and causes excess mortality. Interferon (IFN) treatment of chronic HCV infection in hemodialysis patients results in high sustained virological response (SVR) rates 6 mo after treatment. The authors aimed to identify factors associated with SVR in hemodialysis patients through analysis of individual patient data obtained from systematic review of published literature.Design, setting, participants & measurements: Medline was searched from 1966 through February 2009, and prospective studies describing IFN treatment of hemodialysis patients with chronic HCV infection with published individual patient data were included. To identify factors associated with SVR, logistic regression was applied with adjustment for study.Results: Twenty studies of IFN treatment provided data on 428 patients. Overall SVR was 45% and in univariate analyses was higher with: 1) three million units or higher three times weekly of IFN; 2) treatment for at least 6 mo; 3) treatment completion; 4) lower baseline HCV RNA; 5) female gender; and 6) early virological negativity. Although limited by missing data, these relationships persisted in multivariate regression.Conclusions: SVR is more likely with larger IFN dose, longer treatment duration, treatment completion, female gender, lower HCV RNA and early virological negativity. For appropriate treatment candidates, regimens should consist of three million units of IFN three times weekly for at least 6 mo, with patients encouraged to complete the full course.Hepatitis C virus (HCV) infects an estimated 170 million people worldwide (1). The prevalence of HCV in hemodialysis (HD) patients ranges from 3 to 23% in developed countries (2) and exceeds 50% in some developing countries (3). HCV-infected HD patients have higher mortality rates than noninfected HD patients, with reported relative risks from 1.25 to 1.57 (4,5). Untreated, spontaneous viral clearance occurs in only 0.5% of chronic HCV-infected patients per year (6). The standard measure of treatment success, sustained virological response (SVR), is defined as achieving HCV RNA negativity six months after treatment completion. In non-HD patients, interferon (IFN) monotherapy achieves SVR in 9 to 22% of patients (7–9) but combination pegylated IFN and ribavirin achieves SVR in 50 to 60% (10,11). However, IFN and ribavirin are associated with significant toxicity including influenza-like symptoms, anemia and depression with IFN (7–9), and hemolytic anemia with ribavirin (7,8).Most studies of HCV-infected HD patients have investigated IFN monotherapy. Only recently, studies have explored pegylated IFN or ribavirin (12–18). IFN treatment after kidney transplantation is associated with increased rates of allograft rejection (19,20), so treatment before transplantation is advised (21,22). Our recent meta-analysis of summary data in HCV-infected HD patients demonstrated an overall SVR rate of 41% with IFN (22), higher than rates in IFN-treated non-HD patients (7,8), but rates of treatment discontinuation due to adverse events were also higher (22).Identifying factors associated with a higher likelihood of SVR among HD patients has important implications for selecting treatment candidates and the optimal treatment regimen. In non-HD patients, higher SVR rates are associated with younger age, female gender, lower patient weight, HCV genotypes other than 1, lower baseline HCV RNA, and absence of cirrhosis on liver biopsy (7–11). Early virological response (EVR), defined as a 2-log₁₀ or larger decrease in HCV RNA by the 12^th week of treatment, is a powerful predictor of SVR (23,24).We investigated whether these previously identified factors associated with SVR in non-HD patients could be validated in the HD population. The majority of studies of IFN in HD patients reported individual patient data, allowing us to extend our prior subgroup analysis and meta-regression of summary data (22) to identify factors associated with SVR.