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1.  Circulating TNF Receptors Are Significant Prognostic Biomarkers for Idiopathic Membranous Nephropathy 
PLoS ONE  2014;9(8):e104354.
Idiopathic membranous nephropathy (iMN) is a common cause of nephrotic syndrome in adults. A biomarker to accurately indicate the severity of iMN and predict long-term prognosis is insufficient. Here, we evaluated the clinical significance of circulating tumor necrosis factor receptors (cTNFRs) as prognostic biomarkers of iMN with nephrotic syndrome. A total of 113 patients with biopsy-proven iMN and 43 healthy volunteers were enrolled in this study. Ninety patients with iMN had nephrotic range proteinuria. Levels of cTNFRs were measured by using serum samples collected at the time of initial diagnosis. Levels of cTNFRs were higher in the patients with nephrotic syndrome than in those with subnephrotic range proteinuria or in the healthy volunteers (P for trend <0.001). Estimated glomerular filtration rate and proteinuria tended to worsen as the cTNFRs levels increased. Having a cTNFR1 level within the highest tertile was a significant risk factor for renal progression after adjustment, in comparison with the other tertiles (hazard ratio [HR], 3.39; 95% confidence interval [95% CI], 1.48–7.78; P = 0.004). The cTNFR2 level within the highest tertile also significantly increased the risk of renal progression (HR, 3.29; 95% CI, 1.43–7.54; P = 0.005). Renal tubular TNFRs expression was associated with cTNFRs level. However, the cTNFRs levels were not associated with autoantibody against phospholipase A2 receptor reactivity/levels or treatment response. This study demonstrated that cTNFRs levels at the time of initial diagnosis could predict renal progression in patients with iMN.
PMCID: PMC4123977  PMID: 25098821
2.  Infusion of autologous bone marrow mononuclear cells leads to transient reduction in proteinuria in treatment refractory patients with Idiopathic membranous nephropathy 
BMC Nephrology  2013;14:262.
The current treatment options for idiopathic membranous nephropathy (IMN) carry significant toxicity. In this prospective, observational pilot study, we used single time infusion of bone marrow derived autologous mononuclear cells (MNCs) in adult patients with treatment refractory IMN.
Twelve patients of biopsy proven IMN who had failed a cyclical 6-month regimen of steroid and cyclophosphamide were enrolled in the study. Bone-marrow was harvested from the iliac crest and underwent processing to isolate MNCs. Cells were counted and subjected to viability testing before being infused through a peripheral vein on the same day. After the infusion, subjects were followed up monthly for the next six months. Supportive treatment including angiotensin antagonists and statins was continued throughout the study period.
The proteinuria, serum albumin and creatinine values at entry were 2.97 ± 0.6 gm/1.73 m2/d, 2.27 ± 1.1 gm/l and 0.9 ± 0.8 mg/dl respectively. There was a reduction in proteinuria (p < 0.0001), and increase in serum albumin (p = 0.001) at 1 month, with 64% of the subjects showing >50% reduction in proteinuria. However, the response was ill sustained. At 6 months, only 2 patients had >50% reduction. Serum creatinine remained stable throughout the study period. No infusion related side effects were noted.
Autologous mononuclear cell infusion leads to transitory reduction in proteinuria and improvement in serum albumin in treatment refractory IMN. This effect, however, is transient. Whether this can be overcome by repeated infusion of cultured mesenchymal cells needs to be investigated.
PMCID: PMC4219434  PMID: 24289828
3.  Anti-phospholipase A2 receptor antibody in idiopathic membranous nephropathy: A report from Iranian population 
Journal of Nephropathology  2013;2(4):241-248.
Background: Idiopathic Membranous Nephropathy (iMN) is the most common cause of nephrotic syndrome in adults. Approximately one third of patients with iMN progress to end-stage renal disease. Anti-phospholipase A2-receptor (anti-PLA2R) antibodies are present in patients with iMN and appear to play a role in the pathogenesis of iMN. Objectives: In this study, we explored the prevalence of anti-PLA2R antibodies in a cohort of patients with iMN in Iran. We also sought to determine circulating levels of anti-secretory PLA2 (anti-sPLA2) antibodies in those with anti-PLA2R antibodies.
Patients and Methods: Using an indirect immunofluorescence assay, we measured anti-PLA2R antibodies in a group of patients with iMN in Iran. The serum levels of anti-sPLA2 antibodies were also measured in those with positive results for anti-PLA2R antibodies.
Results: We studied 23 patients with iMN (M/F 12/11, 34±9.8 year), two patients with secondary MN and five patients  with the nephrotic syndrome of other causes.Anti-PLA2R antibodies were detected in 17/23 (74%) of patients with iMN, but not in those with secondary MN or other forms of primary glomerular diseases. We found no correlation between anti-PLA2R antibody titer and the degree of proteinuria. We found high titers of anti-sPLA2 antibodies in a subset of patients with high levels of anti-PLA2R antibodies.
Conclusions: Anti-PLA2R antibodies are specific for iMN. Proteinuria may also reflect glomerular structural damage rather than immunological activity of the disease. The preliminary idea of any presumptive role of anti-sPLA2antibodies in iMN needs further  investigation.
PMCID: PMC3891130  PMID: 24475456
Idiopathic membranous nephropathy; Anti-phospholipase A2-receptor antibodies; Anti-phospholipase A2 antibodies nephrotic syndrom; End-stage renal disease
4.  Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome 
BMC Nephrology  2007;8:11.
Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome.
A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988–2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation.
13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 ± 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 ± 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications – prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 ± 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 ± 3.1. The mean GFRe was 127 ± 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive.
IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.
PMCID: PMC1959515  PMID: 17683621
5.  Effect of steroid and cyclosporine in membranous nephropathy that is resistant to steroid and/or cytotoxic treatment 
Membranous Nephropathy (MN) is a glomerular disease characterized by proteinuria. The etiology is unknown in many cases, while in some patients MN may be secondary to infection, to other diseases, or to exposure to drugs and toxic substances. The prognosis of the disease is variable, 1/3 of patients can have spontaneous remission; patients with nephrotic proteinuria, those with advanced tubulointerstitial changes and those with increased serum creatinine at presentation have a poorer prognosis. Although MN is one of the most common causes of adult-onset Nephrotic Syndrome (NS), its management is still controversial. Corticosteroids have been used for many years as the basic treatment, though with controversial results. Controversial results have been obtained with cytotoxic agents. Cyclosporine has been shown to be effective in the treatment of this disease. We have evaluated the results of 23 patients (14 males, 9 females aged between 26-53) diagnosed with Idiopathic MN (IMN) who have received cyclosporine because of the relapse or persistence after steroid and/or cytotoxic treatment. At the end of a 12-month follow-up, 8 patients had (34.8%) complete remission, 8 (34.8%) had partial remission, 2 (8.7%) had persistent proteinuria and 5 patients (21.7%) had no response to the treatment. There was a significant decrease in proteinuria throughout the study. There was no significant difference in total protein, albumin and creatinine levels between before and after the treatment. Our results indicate that patients with MN who do not respond well or have-relapse after steroid and/or cytotoxic therapy, should be offered cyclosporine. We think that in the future; long-term studies which are prospective and randomized with an extensive number of patients will be effective on the treatment of MN.
PMCID: PMC3902265  PMID: 24482713
Membranous nephropathy; steroid; cyclosporine
6.  Immunosuppressive Treatment for Nephrotic Idiopathic Membranous Nephropathy: A Meta-Analysis Based on Chinese Adults 
PLoS ONE  2012;7(9):e44330.
Idiopathic membranous nephropathy (IMN) is the most common pathological type for nephrotic syndrome in adults in western countries and China. The benefits and harms of immunosuppressive treatment in IMN remain controversial.
To assess the efficacy and safety of different immunosuppressive agents in the treatment of nephrotic syndrome caused by IMN.
PubMed, EMBASE, Cochrane Library and wanfang, weipu, qinghuatongfang, were searched for relevant studies published before December 2011. Reference lists of nephrology textbooks, review articles were checked. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager.
Main Results
17 studies were included, involving 696 patients. Calcineurin inhibitors had a better effect when compared to alkylating agents, on complete remission (RR 1.61, 95% CI 1.13, to 2.30 P = 0.008), partial or complete remission (effective) (CR/PR, RR 1.29, 95% CI 1.09 to 1.52 P = 0.003), and fewer side effects. Among calcineurin inhibitors, tacrolimus (TAC) was shown statistical significance in inducing more remissions. When compared to cyclophosphamide (CTX), leflunomide (LET) showed no beneficial effect, mycophenolate mofetil (MMF) showed significant beneficial on effectiveness (CR/PR, RR: 1.41, 95% CI 1.16 to 1.72 P = 0.0006) but not significant on complete remission (CR, RR: 1.38, 95% CI 0.89 to 2.13 P = 0.15).
This analysis based on Chinese adults and short duration RCTs suggested calcineurin inhibitors, especially TAC, were more effective in proteinuria reduction in IMN with acceptable side effects. Long duration RCTs were needed to confirm the long-term effects of those agents in nephrotic IMN.
PMCID: PMC3434188  PMID: 22957065
7.  Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel 
A synthetic adrenocorticotropin (ACTH) analog has shown efficacy in Europe as primary and secondary therapy for nephrotic syndrome, but there is no published experience using the natural, highly purified ACTH gel formulation, available in the United States, for nephrotic syndrome. We therefore investigated the use of ACTH gel for nephrotic syndrome in the United States.
Patients and methods:
Twenty-one patients with nephrotic syndrome treated with ACTH gel outside of research settings in the United States, with initiation of therapy by December 31, 2009, allowing a minimum 6 months follow-up. We defined complete remission as stable renal function with proteinuria falling to <500 mg/day, and partial remission as stable renal function with >50% reduction in proteinuria from 500 to 3500 mg/day.
Twenty-one patients with nephrotic syndrome were treated: 11 with idiopathic membranous nephropathy (iMN), 4 with membranoproliferative glomerulonephritis (MPGN), 1 with focal segmental glomerulosclerosis (FSGS), 1 with minimal change disease (MCD), 1 with immunoglobulin A (IgA) nephropathy, 1 with class V systemic lupus erythematosus (SLE) glomerulonephritis, 1 with monoclonal diffuse proliferative glomerulonephritis, and 1 with unbiopsied nephrotic syndrome. ACTH was used as primary therapy for 3 patients; the remaining patients had previously failed a mean 2.3 immunosuppressive regimens. Eleven patients achieved a complete or partial remission, with 4 (19%) in complete remission. Of the 11 patients who achieved remission, 9 had iMN, 1 had FSGS, and 1 had IgA nephropathy. Of the 11 patients with iMN, 3 (27%) achieved complete remission and 6 (55%) achieved partial remission despite having previously failed a mean 2.4 therapies. Five patients reported steroid-like adverse effects, but there were no severe infections. The limitations were retrospective data analysis with short-term follow-up.
ACTH gel may be a viable treatment option for resistant nephrotic syndrome due to membranous nephropathy. Short-term data suggest that remission rates may approach 80%.
PMCID: PMC3063118  PMID: 21448451
nephrotic syndrome; membranous nephropathy; chronic kidney disease
8.  Smoking Is a Risk Factor for the Progression of Idiopathic Membranous Nephropathy 
PLoS ONE  2014;9(6):e100835.
Multiple studies have shown cigarette smoking to be a risk factor for chronic kidney disease. However, it is unknown whether smoking similarly increases the risk for progression of membranous nephropathy.
This study used the Nagoya Nephrotic Syndrome Cohort Study (N-NSCS), including 171 patients with idiopathic membranous nephropathy (IMN) from 10 nephrology centers in Japan. The dose-response relationships between cigarette smoking and the outcomes were assessed by using multivariate Cox proportional hazards models adjusted for clinically relevant factors. The primary outcome was a 30% decline in the estimated glomerular filtration rate (eGFR). The secondary outcome was first complete remission (CR) of proteinuria.
During the observation period (median, 37 months; interquartile range, 16–71 months), 37 (21.6%) patients developed a 30% decline in eGFR and 2 (1.2%) progressed to ESRD. CR occurred in 103 (60.2%) patients. Multivariate Cox proportional hazards models revealed current smoking (adjusted hazard ratio [HR], 7.81 [95% confidence interval (CI), 3.17–19.7]), female sex (adjusted HR, 3.58 [95% CI, 1.87–8.00]), older age (adjusted HR, 1.71 [95% CI, 1.13–2.62] per 10 years), the number of cigarettes smoked daily (adjusted HR, 1.61 [95% CI, 1.23–2.09] per 10 cigarettes daily), and cumulative smoking of ≥40 pack-years (adjusted HR, 5.56 [95% CI, 2.17–14.6]) to be associated with a 30% decline in eGFR. However, smoking was not associated with CR.
Smoking is a significant and dose-dependent risk factor for IMN progression. All patients with IMN who smoke should be encouraged to quit.
PMCID: PMC4071015  PMID: 24964146
9.  Patient Age and the Prognosis of Idiopathic Membranous Nephropathy 
PLoS ONE  2014;9(10):e110376.
Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients.
We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65–70 years, and 41 (24.0%) patients ≥71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients.
During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR) = 3.11, 95% confidence interval (CI): 1.45–7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59–242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59–204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51–37.8; P = 0.012).
Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper.
PMCID: PMC4203783  PMID: 25330372
10.  Relapse or Worsening of Nephrotic Syndrome in Idiopathic Membranous Nephropathy Can Occur even though the Glomerular Immune Deposits Have Been Eradicated 
Nephron. Clinical Practice  2011;119(2):c145-c153.
Background: Relapse or worsening of nephrotic syndrome (NS) in idiopathic membranous nephropathy (IMN) is generally assumed to be due to recurrent disease. Here we document that often that may not be the case. Subjects and Methods: This is a prospective study of 7 consecutive IMN patients whose renal status improved, then worsened after completing a course of immunosuppressive therapy. Each underwent detailed testing and repeat kidney biopsy. Results: In 4 patients (group A), the biopsy showed recurrent IMN (fresh subepithelial deposits). Immunosuppressive therapy was begun. In the other 3 patients (group B), the biopsy showed that the deposits had been eradicated. However, the glomerular basement membrane (GBM) was thickened and vacuolated. Immunosuppressive therapy was withheld. Groups A and B were comparable except that group B had very high intakes of salt and protein, based on 24-hour urine testing. Reducing their high salt intake sharply lowered proteinuria to the subnephrotic range and serum creatinine stabilized. Conclusion: This work is the first to demonstrate that relapse/worsening of NS can occur in IMN even though the GBM deposits have been eradicated. High salt and protein intake in combination with thickened and vacuolated GBM appears to be the mechanism.
PMCID: PMC3214955  PMID: 21757952
Relapse of membranous nephropathy; Salt intake; Eradication of GBM deposits
11.  Spironolactone Plus Full-Dose ACE Inhibition in Patients with Idiopathic Membranous Nephropathy and Nephrotic Syndrome: Does It Really Work? 
Pharmaceuticals  2010;3(1):1-9.
We have studied the effects of add-on spironolactone treatment (100 mg/day) in 11 patients with idiopathic membranous nephropathy (IMN) and >3 gm proteinuria/day despite angiotensin converting enzyme (ACE) inhibitor therapy titrated to a systolic/diastolic blood pressure <120/80 mmHg. Blood pressure, 24-hour urinary protein excretion, and creatinine clearance were measured prior to, after two months of combined therapy, and after a 2-month withdrawal period of spironolactone. While systolic and diastolic blood pressure decreased significantly after spironolactone therapy, proteinuria did not improve. Serum potassium increased significantly as well, with three patients requiring resin-binding therapy. Thus, spironolactone seems to have no additional antiproteinuric effects over ACE inhibitor therapy in patients with IMN and nephrotic syndrome and carries the risk of significant hyperkalemia.
PMCID: PMC3991017
idiopathic membranous nephropathy; spironolactone; proteinuria; hyperkalemia
12.  Association of phospholipase A2 receptor 1 polymorphisms with idiopathic membranous nephropathy in Chinese patients in Taiwan 
Idiopathic membranous nephropathy (IMN) is one of the most common forms of autoimmune nephritic syndrome in adults. The purpose of this study is to evaluate whether polymorphisms of PLA2R1 affect the development of IMN.
Taiwanese-Chinese individuals (129 patients with IMN and 106 healthy controls) were enrolled in this study. The selected single nucleotide polymorphisms (SNPs) in PLA2R1 were genotyped by real-time polymerase chain reaction using TaqMan fluorescent probes, and were further confirmed by polymerase chain reaction-restriction fragment length polymorphism. The roles of the SNPs in disease progression were analyzed.
Genotype distribution was significantly different between patients with IMN and controls for PLA2R1 SNP rs35771982 (p = 0.015). The frequency of G allele at rs35771982 was significantly higher in patients with IMN as compared with controls (p = 0.005). In addition, haplotypes of PLA2R1 may be used to predict the risk of IMN (p = 0.004). Haplotype H1 plays a role in an increased risk of IMN while haplotype H3 plays a protective role against this disease. None of these polymorphisms showed a significant and independent influence on the progression of IMN and the risk of end-stage renal failure and death (ESRF/death). High disease progression in patients having C/T genotype at rs6757188 and C/G genotype at rs35771982 were associated with a low rate of remission.
Our results provide new evidence that genetic polymorphisms of PLA2R1 may be the underlying cause of IMN, and the polymorphisms revealed by this study warrant further investigation.
PMCID: PMC2959017  PMID: 20937089
13.  Identification and Characterization of a New Autoimmune Protein in Membranous Nephropathy by Immunoscreening of a Renal cDNA Library 
PLoS ONE  2012;7(11):e48845.
Membranous Nephropathy (MN) represents a large amount of Nephrotic Syndromes in the adult population and its definitive diagnosis is currently carried out through biopsy. An autoimmune condition has been demonstrated in idiopathic MN (iMN) in which some kidney structures are targeted by patient autoantibodies. Some candidate antigens have been described and other likely involved target proteins responsible for the disease are not known yet. In this work our aim is to identify these proteins by screening a lambda-phage library with patients’ sera. We enrolled four groups of patients: two MN groups of 12 full iMN patients; one control group of 15 patients suffering from other renal diseases; one control group of 15 healthy individuals. A commercial cDNA phagemide library was screened using the above described sera, in order to detect positive signals due to antigen-antibody bond. We detected one phagemide clone expressing a protein which was shown to be targeted by the antibodies of the iMN sera only. Control sera were negative. The sequence analysis of cDNA matched the Synaptonemal Complex protein 65 (SC65) coding sequence. Further proteomic analyses were carried out to validate our results. We provide evidence of an involvement of SC65 protein as an autoimmune target in iMN. Considering the invasiveness and the resulting risk coming from renal biopsy, our ongoing aim is to set a procedure able to diagnose affected patients through a little- or non-invasive method such as blood sampling rather than biopsy.
PMCID: PMC3493607  PMID: 23144993
14.  The Relationship between Proteinuria and Coronary Risk: A Systematic Review and Meta-Analysis 
PLoS Medicine  2008;5(10):e207.
Markers of kidney dysfunction such as proteinuria or albuminuria have been reported to be associated with coronary heart disease, but the consistency and strength of any such relationship has not been clearly defined. This lack of clarity has led to great uncertainty as to how proteinuria should be treated in the assessment and management of cardiovascular risk. We therefore undertook a systematic review of published cohort studies aiming to provide a reliable estimate of the strength of association between proteinuria and coronary heart disease.
Methods and Findings
A meta-analysis of cohort studies was conducted to obtain a summary estimate of the association between measures of proteinuria and coronary risk. MEDLINE and EMBASE were searched for studies reporting an age- or multivariate-adjusted estimate and standard error of the association between proteinuria and coronary heart disease. Studies were excluded if the majority of the study population had known glomerular disease or were the recipients of renal transplants. Two independent researchers extracted the estimates of association between proteinuria (total urinary protein >300 mg/d), microalbuminuria (urinary albumin 30–300 mg/d), macroalbuminuria (urinary albumin >300 mg/d), and risk of coronary disease from individual studies. These estimates were combined using a random-effects model. Sensitivity analyses were conducted to examine possible sources of heterogeneity in effect size. A total of 26 cohort studies were identified involving 169,949 individuals and 7,117 coronary events (27% fatal). The presence of proteinuria was associated with an approximate 50% increase in coronary risk (risk ratio 1.47, 95% confidence interval [CI] 1.23–1.74) after adjustment for known risk factors. For albuminuria, there was evidence of a dose–response relationship: individuals with microalbuminuria were at 50% greater risk of coronary heart disease (risk ratio 1.47, 95% CI 1.30–1.66) than those without; in those with macroalbuminuria the risk was more than doubled (risk ratio 2.17, 1.87–2.52). Sensitivity analysis indicated no important differences in prespecified subgroups.
These data confirm a strong and continuous association between proteinuria and subsequent risk of coronary heart disease, and suggest that proteinuria should be incorporated into the assessment of an individual's cardiovascular risk.
Vlado Perkovic and colleagues show, through a systematic review and meta-analysis of cohort studies, that there is a strong and continuous association between proteinuria and subsequent risk of coronary heart disease.
Editors' Summary
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of arteries, the vessels that nourish the organs of the body by carrying blood and oxygen to them. Because they narrow the arteries, atherosclerotic plaques restrict the blood flow to the body's organs. If these plaques form in the arteries that feed the heart muscle (the coronary arteries), the result is CHD. The symptoms of CHD include shortness of breath and chest pains (angina). In addition, if a plaque breaks off the wall of a coronary artery, it can completely block that artery, which kills part of the heart muscle and causes a potentially fatal heart attack. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, being overweight, and being physically inactive are established risk factors for CHD. Treatments for CHD include lifestyle changes (for example, losing weight) and medications that lower blood pressure and blood cholesterol. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
In addition to the established risk factors for CHD, several other factors may also increase a person's risk of developing CHD, including kidney disease, which affects one in six adults to some degree. An early sign of kidney dysfunction is high amounts of a protein called albumin or of total proteins in the urine (albuminuria and proteinuria, respectively). Some studies have suggested that proteinuria is associated with an increased risk of CHD, but the results of these studies are inconsistent. Consequently, it is unclear whether proteinuria should be considered when assessing and managing an individual's CHD risk. In this study, the researchers undertake a systematic review (a study in which predefined search criteria are used to identify all the research on a specific topic) and a meta-analysis (a statistical method for combining the results of several studies) of published studies that have investigated the association between proteinuria and CHD.
What Did the Researchers Do and Find?
The researchers' systematic review identified 26 published studies that provided estimates of the association between CHD risk and proteinuria and albuminuria by measuring baseline urinary protein and albumin levels in people who were then followed for several years to see whether they developed CHD. Nearly 170,000 individuals participated in these studies, which recorded more 7,000 fatal and nonfatal heart attacks and other coronary events. In the meta-analysis, proteinuria (urinary protein of more than 300 mg/d or dipstick 1+ or more) increased CHD risk by 50% after adjustment for other known CHD risk factors. Furthermore, individuals with microalbuminuria (a urinary albumin of 30–300 mg/d) were 50% more likely to develop CHD than those with normal amounts of urinary albumin; people with macroalbuminuria (urinary albumin of more than 300 mg/d) were more than twice as likely to develop CHD. Finally, the association between proteinuria and CHD did not differ substantially between specific subgroups of participants such as people with and without diabetes.
What Do These Findings Mean?
These findings suggest that there is a strong, possibly dose-dependent association between proteinuria and the risk of CHD and that this association is independent of other known CHD risk factors, including diabetes. The finding that people with proteinuria have a 50% or greater increased risk of developing CHD than people without proteinuria may be a slight overestimate of the strength of the association between proteinuria because of publication bias. That is, studies that failed to show an association may not have been published. However, because this systematic review and meta-analysis includes several large population-based studies done in various parts of the world, these findings are likely to be generalizable. Thus, these findings support the inclusion of an evaluation of proteinuria in the assessment of CHD risk and suggest that medications and other strategies that reduce proteinuria might help to reduce the overall burden of CHD.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has pages on coronary heart disease, atherosclerosis, and chronic kidney failure (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease
The UK National Health Service Direct health encyclopedia also provides information about coronary heart disease (in several languages)
Information for patients and caregivers is provided by the American Heart Association on all aspects of heart disease.
The British Heart Foundation also provides information on heart disease and on keeping the heart healthy
PMCID: PMC2570419  PMID: 18942886
15.  A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar® Gel) in nephrotic syndrome due to idiopathic membranous nephropathy 
Nephrology Dialysis Transplantation  2014;29(8):1570-1577.
H.P. Acthar® Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar® Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy.
Twenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. Changes in proteinuria, albumin, cholesterol profile, estimated glomerular filtration rate and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety.
Baseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated glomerular filtration rate (77 ± 30 mL/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (P < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A >50% decrease in proteinuria was noted in 65% of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients.
H.P. Acthar® Gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.
PMCID: PMC4106642  PMID: 24714414
ACTH (H.P. Acthar® Gel); membranous nephropathy; nephrotic syndrome
16.  Antiphospholipase A2 Receptor Autoantibodies: A Comparison of Three Different Immunoassays for the Diagnosis of Idiopathic Membranous Nephropathy 
Journal of Immunology Research  2014;2014:143274.
Background. The recent identification of circulating autoantibodies directed towards the M-type phospholipase A2 receptor (PLA2R) has been a major advancement in the serological diagnosis of idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults. The goal of this study was to compare the performance characteristics of two commercial assays as well as the first addressable laser bead immunoassay (ALBIA) developed for the detection of anti-PLA2R antibodies. Methods. Serum samples of 157 IMN patients and 142 controls were studied. Samples were tested by a cell based immunofluorescence assay (CBA-IFA, Euroimmun, Germany), by ELISA (Euroimmun), and by a novel ALBIA employing an in vivo expressed recombinant human PLA2R. Results. Overall, the three assays showed significant qualitative and quantitative correlation. As revealed by receiver operating characteristic analysis, the ALBIA correlated better with the CBA-IFA than the ELISA (P = 0.0003). The clinical sensitivities/specificities for IMN were 60.0% (51.0–68.5%)/98.6% (95.0–99.8%) and 56.2% (47.2–64.8%)/100.0% (97.4–100.0%) for ALBIA and CBA-IFA, respectively. Conclusion. The ALBIA represents a promising assay for the detection of anti-PLA2R antibodies showing similar performance to the CBA-IFA and the advantage of ease of use and suitability for high throughput, rapid turnaround times, and multiplexing.
PMCID: PMC4000632  PMID: 24812637
17.  TRPC6 Single Nucleotide Polymorphisms and Progression of Idiopathic Membranous Nephropathy 
PLoS ONE  2014;9(7):e102065.
Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN.
Methods & Results
Genomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n = 26, renal failure n = 46, persistent proteinuria n = 29, follow-up median 80 months {range 51–166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors.
Our data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN.
PMCID: PMC4096511  PMID: 25019165
18.  PLA2R Antibody Levels and Clinical Outcome in Patients with Membranous Nephropathy and Non-Nephrotic Range Proteinuria under Treatment with Inhibitors of the Renin-Angiotensin System 
PLoS ONE  2014;9(10):e110681.
Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39–9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.
PMCID: PMC4197007  PMID: 25313791
19.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
PMCID: PMC3445446  PMID: 23028261
20.  Immediate versus delayed intramedullary nailing for open fractures of the tibial shaft: A multivariate analysis of factors affecting deep infection and fracture healing 
Indian Journal of Orthopaedics  2008;42(4):410-419.
The purpose of this study was to evaluate contributing factors affecting deep infection and fracture healing of open tibia fractures treated with locked intramedullary nailing (IMN) by multivariate analysis.
Materials and Methods:
We examined 99 open tibial fractures (98 patients) treated with immediate or delayed locked IMN in static fashion from 1991 to 2002. Multivariate analyses following univariate analyses were derived to determine predictors of deep infection, nonunion, and healing time to union. The following predictive variables of deep infection were selected for analysis: age, sex, Gustilo type, fracture grade by AO type, fracture location, timing or method of IMN, reamed or unreamed nailing, debridement time (≤6 h or >6 h), method of soft-tissue management, skin closure time (≤1 week or >1 week), existence of polytrauma (ISS< 18 or ISS≥18), existence of floating knee injury, and existence of superficial/pin site infection. The predictive variables of nonunion selected for analysis was the same as those for deep infection, with the addition of deep infection for exchange of pin site infection. The predictive variables of union time selected for analysis was the same as those for nonunion, excluding of location, debridement time, and existence of floating knee and superficial infection.
Six (6.1%; type II Gustilo n=1, type IIIB Gustilo n=5) of the 99 open tibial fractures developed deep infections. Multivariate analysis revealed that timing or method of IMN, debridement time, method of soft-tissue management, and existence of superficial or pin site infection significantly correlated with the occurrence of deep infection (P< 0.0001). In the immediate nailing group alone, the deep infection rate in type IIIB + IIIC was significantly higher than those in type I + II and IIIA (P = 0.016). Nonunion occurred in 17 fractures (20.3%, 17/84). Multivariate analysis revealed that Gustilo type, skin closure time, and existence of deep infection significantly correlated with occurrence of nonunion (P < 0.05). Gustilo type and existence of deep infection were significantly correlated with healing time to union on multivariate analysis (r2 = 0.263, P = 0.0001).
Multivariate analyses for open tibial fractures treated with IMN showed that IMN after EF (especially in existence of pin site infection) was at high risk of deep infection, and that debridement within 6 h and appropriate soft-tissue managements were also important factor in preventing deep infections. These analyses postulated that both the Gustilo type and the existence of deep infection is related with fracture healing in open fractures treated with IMN. In addition, immediate IMN for type IIIB and IIIC is potentially risky, and canal reaming did not increase the risk of complication for open tibial fractures treated with IMN.
PMCID: PMC2740339  PMID: 19753228
Deep infection; fracture healing; intramedullary nailing; multivariate analysis; open tibial fracture; predictive factors
21.  Coexistence of ANCA-associated glomerulonephritis and anti-phospholipase A2 receptor antibody-positive membranous nephropathy 
Clinical Kidney Journal  2012;5(2):162-165.
Antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) have been demonstrated to mediate anti-neutrophil cytoplasmic antibody (ANCA)-associated disease. For membranous nephropathy, antibodies to the podocyte-expressed phospholipase A2 receptor (anti-PLA2R) are highly associated with disease activity and have been reported in at least 70% of patients with idiopathic membranous nephropathy (IMN). We present a case of a 56-year-old male with a 1 year history of hypertension, leg edema, and proteinuria, who presented with advanced renal failure and was found to have both ANCA-associated glomerulonephritis (GN) and IMN on kidney biopsy. Consistent with the idea that this is due to the chance occurrence of two independent diseases, we found both anti-MPO and anti-PLA2R antibodies in the patient's sera. Treatment with methylprednisolone, plasmapheresis, and cyclophosphamide resulted in improvement in kidney function and proteinuria, together with the simultaneous decrease in both autoantibodies. This is the first demonstration of two pathogenic antibodies giving rise to ANCA-associated GN and IMN in the same patient. It confirms the importance of classifying disease based upon the underlying mechanism, in addition to renal histopathology, to both optimize therapy and predict prognosis.
PMCID: PMC3341840  PMID: 22833809
ANCA vasculitis; antiphospholipase; membranous nephropathy
22.  The Diagnosis Accuracy of PLA2R-AB in the Diagnosis of Idiopathic Membranous Nephropathy: A Meta-Analysis 
PLoS ONE  2014;9(8):e104936.
The presence of antibodies against the M-type phospholipase A2 receptor (PLA2R-AB) is considered to be a promising serological diagnostic biomarker of idiopathic membranous nephropathy (iMN). However, controversy remains about the diagnostic accuracy of serum PLA2R-AB testing. Here, we performed a comprehensive meta-analysis to assess the overall diagnostic value of serum PLA2R-AB testing in iMN detection.
PubMed, Embase, and CNKI (Chinese National Knowledge Infrastructure) were searched for relevant original articles through January 31, 2014. The summary sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio (DOR) were estimated using the bivariate model. The heterogeneity among studies was explored by subgroup and meta-regression analysis.
9 articles, including 15 studies, were eventually identified with a total of 2212 patients. The summary sensitivity of all studies is 78% (95% CI: 66% to 87%) and the specificity is 99% (95% CI: 96% to 100%). The summary positive and negative likelihood ratios are 96.1 (95% CI, 19.5 to 472.1) and 0.22 (95% CI: 0.14 to 0.35), respectively. The DOR is 437 (95%CI, 74 to 2592). The subgroup analysis and meta-regression suggest the test interval is the main source of heterogeneity.
Serum PLA2R-AB testing is a useful tool to detect iMN. In addition, considering the high heterogeneity and potential publication bias, further high quality studies are needed in the future.
PMCID: PMC4138154  PMID: 25136841
23.  Ponticelli regimen in idiopathic nephrotic syndrome 
Indian Journal of Nephrology  2009;19(2):48-52.
Various studies have demonstrated that treatment with methyl prednisolone and chlorambucil could increase the chance of remission of idiopathic nephrotic syndrome (INS) of varied histology in patients who do not respond to the conventional treatment. This study was done to assess the safety and efficacy of methyl prednisolone and chlorambucil regimen in patients with various types of glomerulonephritides which were resistant to the usual conventional immunosuppressive drugs. Thirty nine patients were treated between June 1998 and December 2003 with Ponticelli regimen for six months. Twenty three patients (58.98%) were men and 16 (41.02%) were women. Mean age at the onset of NS was 23.59 ± 1.28 (range 10-51) years. Four patients (10.2%) had minimal change disease (MCD), six patients (15.4%) had membranoproliferative glomerulonephritis (MPGN), two (5.1%) had IgA nephropathy, and 18 patients (46.1%) had focal segmental glomerulosclerosis (FSGS). Eleven patients were excluded from the final analysis. Of the remaining 28 patients, mean baseline proteinuria was 3.31 ± 3.09 g/day. Mean baseline plasma albumin was 2.84 ± 1.002 g/dl and mean baseline serum creatinine was 0.87 ± 0.42 mg/dl. At the end of six months of treatment, mean proteinuria was 1.02 ± 0.85 g/day. Mean plasma albumin was 3.69 ± 0.78 g/day, and mean serum creatinine was 0.85 ± 0.26 mg/dl. Mean followup was 13.21 ± 7.7 times in 18.92 ± 12.58 months. At the end of six months of treatment, seven patients (25%) achieved complete remission (CR), 10 patients (35.71%) partial remission (PR), and 11 patients (39.3%) did not show any response to the therapy. Most of the patients in responder group had FSGS (64.70%), whereas in nonresponder group patients had MPGN and mesangioproliferative glomerulonephritis (MesPGN). Out of 13 FSGS cases five (38.46%) achieved CR, six (46.15%) PR, and only two (15.38%) failed to respond. The incidence of side effects was 39.3%. Responders had more side effects than nonresponders (47 vs 27.3%). Methyl prednisolone and chlorambucil therapy (Ponticelli regimen) is safe and efficacious in achieving remission in significant number of INS patients other than membranous nephropathy, without any serious side effect on short term followup. However, a longer followup is required to demonstrate the sustained efficacy and long-term side effect of this regimen.
PMCID: PMC2847807  PMID: 20368923
Idiopathic nephrotic syndrome; Ponticelli regimen; prednisolone; chlorambucil
24.  Proteinuria: an ignored marker of inflammation and cardiovascular disease in chronic hemodialysis 
Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis (HD) patients, the main etiologies being diabetes and hypertension. Cardiac and inflammatory biomarkers are usually employed to assess risk or damage, or during follow-up. Proteinuria is considered a strong predictor of morbidity, a cause of inflammation, oxidative stress, hemodynamic alteration, and progression of chronic kidney disease. However, proteinuria is rarely considered in the clinical assessment of HD patients.
This was a concurrent, cohort-observational, cross-sectional study in which 52 chronic HD subjects were divided into three groups according to the degree of proteinuria: Group (G) A: <1 g/day, n = 25; GB: 1–3 g/day, n = 13; GC: >3 g/day, n = 14. Baseline hemoglobin, albuminemia, cholesterol, body mass index, Malnutrition-Inflammatory Score, pro-B-type natriuretic peptide, troponin T, C-reactive protein (CRP), and ultrafiltration rates were analyzed.
There was no difference between groups in terms of baseline age, gender, hypertension, cause of renal failure, hemoglobin, cholesterol, albumin, CRP levels, cardiac biomarkers, adiponectin, body mass index, or Malnutrition-Inflammatory Score. Time on HD: GA, 34.56 ± 23.3 (range [r]: 6–88); GB, 25.15 ± 19.40 (r: 6–58); GC, 18.21 ± 9.58 (r: 6–74) months; P = 0.048. Proteinuria: GA, 0.33 ± 0.30 (r: 0.0–0.88); GB, 1.66 ± 0.54 (r: 1.03–2.75); GC, 7.18 ± 2.80 (r: 3.04–21.5) g/day; P < 0.001. Mean ultrafiltration rates were significantly different: GA, 2.80 ± 0.73; GB: 1.85 ± 0.96 liters/session; P = 0.003. Fourteen diabetic patients were identified (27%): GA, 3 (12%); GB, 3 (23%); GC, 8 (57%); P = 0.009. A positive and significant correlation was observed between diabetes and proteinuria >3 g/day: rho 0.438, P = 0.027. Although troponin T, pro-B-type natriuretic peptide, adiponectin, and CRP were not different among groups, the positive correlation between troponin T and CRP elevated significantly as proteinuria increased: GA, rho 377, P = 0.063; GB, rho 663, P = 0.013; GC, rho 687, P = 0.007.
In chronic HD, nephrotic-range proteinuria was significantly higher in diabetic nephropathy patients versus other causes. This was associated with inflammation and cardiac stress and was independent of fluid removal. Proteinuria >3 g/day was associated with shorter time on HD. Whether severe proteinuria is associated with shorter survival in HD, independent of diabetes, is to be determined. Proteinuria should be considered in the assessment of cardiovascular and inflammatory states in HD patients.
PMCID: PMC3278252  PMID: 22334794
hemodialysis; proteinuria; inflammation; cardiovascular risk
25.  The Association of Reamed Intramedullary Nailing and Long-Term Cognitive Impairment 
Journal of orthopaedic trauma  2011;25(12):707-713.
To examine the association of reamed intramedullary nailing (IMN) and long-term cognitive impairment in trauma intensive care unit (TICU) survivors.
Prospective observational cohort.
Academic Level-1 Trauma Center.
173 patients with multiple trauma (Injury Severity Score (ISS) >15) who presented to a Level I TICU from July 2006 to July 2007 without evidence of intrancranial hemorrhage (ICH)
Main Outcome Measure
Twelve-month cognitive impairment defined a priori as 2 neuropsychological test scores 1.5 SD below the mean or 1 neuropsychological test score 2 SD below the mean.
108/173 patients (62.4%) were evaluated 12-months after injury with a comprehensive battery of neuropsychological tests. There were 18 patients who received a reamed IMN and 14/18 (78%) of these patients had cognitive deficit at follow-up. Fracture treatment with a reamed IMN was associated with long-term impairment (27.4% vs. 8.2%, p= 0.03). Multivariable logistic regression found that a reamed IMN (OR: 3.2, 95% CI: 0.95-10.9; p=0.06) was a moderate risk factor for the development of cognitive impairment 12-months after injury, after controlling for ISS, level of education, intra-operative hypotension, and duration of mechanical ventilation.
Fracture fixation with a reamed IMN is moderately associated with cognitive impairment in this cohort of multiple trauma patients without ICH at 1-year post-injury. Orthopaedic trauma research should continue to investigate a potential association of acute fracture management and long-term cognitive outcome.
PMCID: PMC3912993  PMID: 22089759
Reamed Intramedullary Nail; Long-Bone Fracture; Polytrauma; Long-Term Cognitive Impairment

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