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ABSTRACT: To compare the usefulness of 3 currently used classification systems in predicting the outcomes of treatment resistance, disease relapse, end-stage renal disease (ESRD), and death in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
Three classification systems were applied to 502 patients with biopsy-proven AAV: 1) the Chapel Hill Consensus Conference (CHCC) definition with categories for granulomatosis with polyangiitis (GPA) (Wegener's), microscopic polyangiitis (MPA), and kidney-limited disease; 2) the European Medicines Agency (EMA) system with categories for GPA and MPA; and 3) classification based on ANCA with specificity for myeloperoxidase (MPO ANCA) versus ANCA with specificity for proteinase 3 (PR3 ANCA). Outcomes included treatment resistance, relapse, ESRD, and death. Proportional hazards models were compared between systems using an information-theoretic approach to rank models by predictive fit. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) and P values are reported.
ANCA specificity was predictive of relapse, with PR3 ANCA-positive patients almost twice as likely to relapse as those with MPO ANCA (HR 1.89 [95% CI 1.33-2.69], P = 0.0004), and ANCA specificity had the best predictive model fit (model rank 1) compared to the CHCC and EMA systems. The CHCC and EMA systems did not predict relapse. By ANCA specificity, categories of GPA, MPA, and kidney-limited disease did not distinguish differences in probability of relapse-free survival. None of the systems predicted treatment resistance, ESRD, or death.
ANCA specificity independently predicts relapse among patients with AAV with renal disease. Classification and diagnostic systems that incorporate ANCA specificity, such as PR3 ANCA-positive MPA and MPO ANCA-positive MPA, provide a more useful tool than the clinical pathologic category alone for predicting relapse.
Arthritis & Rheumatism 10/2012; 64(10):3452-62. · 7.87 Impact Factor
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Yali Cao,
Jiajin Yang,
Kerry Colby,
Susan L Hogan,
Yichun Hu, Caroline E Jennette,
Elisabeth A Berg,
Youkang Zhang,
J Charles Jennette,
Ronald J Falk,
Gloria A Preston
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ABSTRACT: Consequences of expression of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gain-of-function variant were evaluated in leukocytes from patients with anti-neutrophil cytoplasmic autoantibody (ANCA) disease. The frequency of the gain-of-function allele within the Caucasian patient cohort was 22% (OR 1.45), compared to general American Caucasian population (16.5%, p = 0.03). Examination of the basal phosphatase activity of PTPN22 gain-of-function protein indicated persistently elevated activity in un-stimulated peripheral leukocytes, while basal activity was undetectable in leukocytes from patients without the gain-of-function variant. To examine consequences of persistently high PTPN22 activity, the activation status of ERK and p38 MAPK were analyzed. While moderate levels of activated ERK were observed in controls, it was undetectable in leukocytes expressing PTPN22 gain-of-function protein and instead p38MAPK was up-regulated. IL-10 transcription, reliant on the ERK pathway, was negatively affected. Over the course of disease, patients expressing variant PTPN22 did not show a spike in IL-10 transcription as they entered remission in contrast to controls, implying that environmentally triggered signals were blunted. Sustained activity of PTPN22, due to the gain-of-function mutation, acts as a dominant negative regulator of ERK activity leading to blunted cellular responsiveness to environmental stimuli and expression of protective cytokines.
PLoS ONE 01/2012; 7(8):e42783. · 4.09 Impact Factor
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ABSTRACT: The optimal course of glucocorticoid therapy in anti-neutrophil cytoplasmic autoantibody (ANCA) disease is unknown. This cohort study evaluates effects of glucocorticoid therapy duration on patient outcomes and adverse events.
This study assessed 147 patients diagnosed between January 1, 2000 and January 1, 2009 who were treated with glucocorticoids and cyclophosphamide. Patients with end stage kidney disease at presentation, treatment resistance, or who had died within 6 months were excluded. Patients were divided into three groups: 0, 5, or >5 mg prednisone daily at 6 months after therapy initiation. The latter two groups were combined for assessment of adverse events. Wilcoxon rank sum, Kruskal-Wallis, or Fisher's exact tests were used for between-group comparisons. Time to relapse was evaluated by the Kaplan-Meier method with log-rank test for comparison.
There were no differences between groups in ANCA specificity, serum creatinine, frequency of risk factors for relapse, or length of therapy with immunosuppressants. Length of glucocorticoid therapy had no impact on time to relapse (hazard ratio, 0.69 [95% confidence interval (CI), 0.23-2.02]; 1.01, [95% CI, 0.57-1.81] for the 5-mg and >5-mg groups, respectively), relapse-free survival, end stage kidney disease, or death. Patients receiving glucocorticoids beyond 6 months had significantly higher incidence of infections (0.64 infections per person-year versus 0.39, P<0.0001) and a marginally significant higher frequency of new-onset diabetes mellitus (odds ratio, 2.03; 95% CI, 0.94-4.38).
Glucocorticoid therapy beyond 6 months is associated with a significantly greater risk of infections but not a significantly decreased risk of relapse.
Clinical Journal of the American Society of Nephrology 12/2011; 7(2):240-7. · 5.23 Impact Factor
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Sophia Lionaki,
Vimal K Derebail,
Susan L Hogan,
Sean Barbour,
Taewoo Lee,
Michelle Hladunewich,
Allen Greenwald,
Yichun Hu, Caroline E Jennette,
J Charles Jennette,
Ronald J Falk,
Daniel C Cattran,
Patrick H Nachman,
Heather N Reich
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ABSTRACT: The aims of this study were to determine the frequency of venous thromboembolic events in a large cohort of patients with idiopathic membranous nephropathy and to identify predisposing risk factors.
We studied patients with biopsy-proven membranous nephropathy from the Glomerular Disease Collaborative Network (n=412) and the Toronto Glomerulonephritis Registry (n=486) inception cohorts. The cohorts were pooled after establishing similar baseline characteristics (total n=898). Clinically apparent and radiologically confirmed venous thromboembolic events were identified. Potential risk factors were evaluated using multivariable logistic regression models.
Sixty-five (7.2%) subjects had at least one venous thromboembolic event, and this rate did not differ significantly between registries. Most venous thromboembolic events occurred within 2 years of first clinical assessment (median time to VTE = 3.8 months). After adjusting for age, sex, proteinuria, and immunosuppressive therapy, hypoalbuminemia at diagnosis was the only independent predictor of a venous thromboembolic event. Each 1.0 g/dl reduction in serum albumin was associated with a 2.13-fold increased risk of VTE. An albumin level <2.8 g/dl was the threshold below which risk for a venous thromboembolic event was greatest.
We conclude that clinically apparent venous thromboembolic events occur in about 7% of patients with membranous nephropathy. Hypoalbuminemia, particularly <2.8 g/dl, is the most significant independent predictor of venous thrombotic risk.
Clinical Journal of the American Society of Nephrology 11/2011; 7(1):43-51. · 5.23 Impact Factor
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Yali Cao,
John L Schmitz,
Jiajin Yang,
Susan L Hogan,
Donna Bunch,
Yichun Hu, Caroline E Jennette,
Elisabeth A Berg,
Frank C Arnett,
J Charles Jennette,
Ronald J Falk,
Gloria A Preston
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ABSTRACT: Anti-neutrophil cytoplasmic autoantibody (ANCA) disease rarely occurs in African Americans and risk factors for the disease in this population are unknown. Here, we genotyped MHC class II alleles and found that, among African Americans, those with proteinase 3-ANCA (PR3-ANCA) had 73.3-fold higher odds of having HLA-DRB1*15 alleles than community-based controls (OR 73.3; 95% CI 9.1 to 591). In addition, a disproportionate number of African American patients carried the DRB1*1501 allelic variant of Caucasian descent rather than the DRB1*1503 allelic variant of African descent. Among Caucasians, those with PR3-ANCA had 2.2-fold higher odds of carrying DRB1*1501 than controls (OR 2.2; 95% CI 1.2 to 4.0). A validation study supported by the Vasculitis Clinical Research Consortium confirmed the strong association between the DRB1*15 allele and PR3-ANCA disease, among African Americans. Furthermore, we found that DRB1*1501 protein binds with high affinity to amino acid sequences of sense-PR3, purportedly an antigenic epitope, and to the amino acid sequence complementary to this epitope in vitro. Peptides of sense-PR3 and complementary-PR3 also bound to TNF-α-induced surface expression of DRB1*1501 on peripheral neutrophils. Taken together, these data suggest HLA-DRB1*15 alleles contribute to the pathogenesis of PR3-ANCA disease.
Journal of the American Society of Nephrology 06/2011; 22(6):1161-7. · 9.66 Impact Factor
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ABSTRACT: The United States Renal Data System (USRDS) is a commonly utilized database for epidemiologic research of ESRD patients. USRDS uses Medical Evidence Form 2728 to collect medical information about ESRD patients. The validity of the Form 2728 "primary cause of renal failure" field for glomerular diseases has not been evaluated, although inconsistencies between Form 2728 information and medical records have been documented previously with respect to comorbidities.
Form 2728 information was linked with renal biopsy results from the Glomerular Disease Collaborative Network (GDCN) for 217 patients with biopsy-confirmed glomerular diseases who had reached ESRD. Biopsy results were compared with the Form 2728 "primary cause of renal failure" field. Diseases were considered individually, and also categorized into commonly used disease groups. Percentage of agreement and disease-specific measures of validity were calculated.
Overall agreement between renal biopsy and Form 2728 was low (14.8% overall, 23.0% when categorized). Agreement was better after Form 2728 was revised in 1995 (10.0% before versus 23.2% after overall). The cause of ESRD field was left blank in 57% of the forms submitted for glomerular disease patients. Individual glomerular diseases had very low specificities, but tended to have high positive predictive values.
Form 2728 does not accurately reflect the renal pathology diagnosis as captured by biopsy. The large degree of missing data and misclassification should be of concern to those performing epidemiologic research using Form 2728 information on glomerular diseases.
Clinical Journal of the American Society of Nephrology 11/2010; 5(11):2046-52. · 5.23 Impact Factor
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Kidney International 03/2010; 77(5):468-9. · 6.61 Impact Factor
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ABSTRACT: Antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis frequently affects the kidney. Here we describe the rates of infection, disease relapse, and death in patients with ANCA small-vessel vasculitis before and after end-stage renal disease (ESRD) in an inception cohort study and compare them to those of patients with preserved renal function. All patients had biopsy-proven ANCA small-vessel vasculitis. Fisher's exact tests and Wilcoxon rank sum tests were used to compare the characteristics by ESRD status. ESRD follow-up included time on dialysis with transplants censored. Over a median follow-up time of 40 months, 136 of 523 patients reached ESRD. ESRD was associated with new-onset ANCA small-vessel vasculitis in 51% of patients, progressive chronic kidney disease without active vasculitis in 43%, and renal relapse in 6% of patients. Relapse rates of ANCA small-vessel vasculitis, reported as episodes/person-year, were significantly lower on chronic dialysis (0.08 episodes) compared with the rate of the same patients before ESRD (0.20 episodes) or with patients with preserved renal function (0.16 episodes). Infections were almost twice as frequent among patients with ESRD on maintenance immunosuppressants and were an important cause of death. Given the lower risk of relapse and higher risk of infection and death, we suggest that immunosuppression be geared to patients with ESRD who present with active vasculitis.
Kidney International 07/2009; 76(6):644-51. · 6.61 Impact Factor
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Nephrology Dialysis Transplantation 06/2008; 23(5):1766-8; author reply 1768. · 3.40 Impact Factor
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ABSTRACT: Case reports have described the onset of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (ANCA SVV) with use of anti-thyroid agents, but an association with thyroid disease in general has not been described. This association was evaluated in a southeastern US population-based case-control study.
Cases (n = 158) had ANCA SVV with biopsy-proven glomerular involvement. Controls (n = 99) were frequency matched by age, gender and state. Use of drugs and comorbidities prior to diagnosis of ANCA SVV were assessed by telephone interview. Information on medications used for thyroid conditions was available in a subset of cases (n = 129). Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Estimates among females were also of interest.
History of thyroid disease was reported in 31 cases (20%) and 7 controls (7%) (OR = 3.7; 95% CI 1.5-9.2; P = 0.005); among females 25/65 (38%) cases and 5/53 (9%) controls (OR = 5.6; 95% CI 1.9-16.8; P = 0.002). Use of anti-thyroid agents was reported in 2 cases and 0 controls (OR not calculable). Among cases, myeloperoxidase (MPO)-ANCA was more common (86%) than proteinase 3 (PR3)-ANCA in those with a history of thyroid disease than those without (53%) (P = 0.007).
Thyroid disease was associated with ANCA SVV, especially among women, and was most frequently associated with MPO-ANCA. The specific diagnosis and detailed clinical history of thyroid disease were not known; a limitation of the study. Use of anti-thyroid agents was uncommon. The association of thyroid disease with ANCA SVV may reflect a propensity for autoimmune disease.
Nephrology Dialysis Transplantation 01/2008; 22(12):3508-15. · 3.40 Impact Factor
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ABSTRACT: Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with a category of small-vessel vasculitis (SVV) with frequent glomerulonephritis. The goal of this study was to evaluate the association of lifetime silica exposure with development of ANCA-SVV, with particular attention to exposure dosage, intensity, and time since last exposure. A southeastern United States, population-based, case-control study was conducted. Case patients had ANCA-SVV with pauci-immune crescentic glomerulonephritis. Population-based control subjects were frequency-matched to case patients by age, gender, and state. Jobs were assessed in a telephone interview. Silica exposure scores incorporated exposure duration, intensity, and probability for each job and then were categorized as none, low/medium, or high lifetime exposure. Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Silica exposure was found in 78 (60%) of 129 case patients and in 49 (45%) of 109 control subjects. There was no increased risk for disease from low/medium exposure relative to no exposure (OR 1.0; 95% CI 0.4 to 2.2) but increased risk with high exposure (OR 1.9; 95% CI 1.0 to 3.5; P = 0.05). Crop harvesting was associated with elevated risk (OR 2.5; 95% CI 1.1 to 5.4; P = 0.03). However, both agricultural and traditional occupational sources contributed to the cumulative silica exposure scores; therefore, the overall effect could not be attributed to agricultural exposures alone. There was no evidence of decreasing by duration of time since last exposure. High lifetime silica exposure was associated with ANCA-SVV. Exposure to silica from specific farming tasks related to harvesting may be of particular importance in the southeastern United States. Interval of time since last exposure did not influence development of ANCA-SVV.
Clinical Journal of the American Society of Nephrology 04/2007; 2(2):290-9. · 5.23 Impact Factor
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ABSTRACT: Predictors of treatment resistance and relapse have not been well described in antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis.
To identify clinical, pathologic, and serologic predictors of treatment resistance and relapse in a community-based cohort of patients with ANCA-associated vasculitis.
Cohort of patients identified at or near the time of biopsy diagnosis and followed as clinically indicated.
The Glomerular Disease Collaborative Network.
350 patients who received a new diagnosis of ANCA-associated vasculitis between 1985 and 2003 and were followed for a median of 49 months.
Patients were categorized according to whether they had antiproteinase-3 (anti-PR3) antibodies or antimyeloperoxidase (anti-MPO) antibodies. Organ involvement was determined by biopsy or by well-defined clinical criteria. Treatment resistance was defined as progressive decline in kidney function with active urine sediment or the persistence or appearance of extrarenal manifestations. Relapse was defined as the time to the resurgence of vasculitic symptoms.
Treatment resistance affected 23% of 334 treated patients and was associated with female sex, black ethnicity, and presentation with severe kidney disease (odds ratio per serum creatinine elevation of 100 micromol/L [1.13 mg/dL], 1.28 [95% CI, 1.16 to 1.39]). The following factors were associated with relapse in 258 (77%) patients who attained remission: seropositivity for anti-PR3 antibodies (hazard ratio, 1.87 [CI, 1.11 to 3.14]) and disease of the lung (hazard ratio, 1.71 [CI, 1.04 to 2.81]) or upper respiratory tract (hazard ratio, 1.73 [CI, 1.04 to 2.88]). Relapses occurred in 26% of patients with no risk factors versus 73% of patients with all 3 risk factors (hazard ratio, 3.7 [CI, 1.4 to 9.7]). Among 143 patients attaining remission who subsequently stopped all immunosuppressant therapy, relapse rates were similar for those who had received cyclophosphamide therapy for 6 months or less (34%) compared with those treated for a longer duration (35%), even after adjusting for risk factors for relapse (hazard ratio, 1.41 [CI, 0.80 to 2.50]).
The cohort mostly included patients with biopsy-proven kidney disease. Patients were not followed with uniform treatment protocols, and only limited information about their clinical course before diagnosis was available.
Female or black patients, or those with severe kidney disease, may be resistant to initial treatment more often than other patients with ANCA-associated small-vessel vasculitis. Increased risk for relapse appears to be related to the presence of lung or upper airway disease and anti-PR3 antibody seropositivity.
Annals of internal medicine 12/2005; 143(9):621-31. · 16.73 Impact Factor
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ABSTRACT: To outline the Kidney Education Outreach Program (KEOP) screening protocol, to describe the context in which these chronic kidney disease (CKD) screenings were administered, and to report the characteristics and screening results for participants from October 2005 to September 2008.
A cohort of 1742 people participated in targeted, free, community-based CKD screenings. Screenings included a self-report questionnaire regarding sociodemographic information, lifestyle behaviors, and personal and family health history. This survey was followed by urine dipstick testing for proteinuria and microalbuminuria.
Medical histories were provided by 1694 individuals: 1522 through the complete questionnaire and 172 through an abbreviated questionnaire that differed principally in lack of information on family history of disease. Urine samples were collected from 1706 participants. The mean age of screening participants was 54 years old; 70% were female, 50% were African American, and 13% were Latino. More than 40% of subjects were obese. Roughly one-quarter (23%) had been diagnosed with diabetes mellitus and about half (47%) had been diagnosed with hypertension. Twenty-four percent reported a family history of kidney disease. While 60% of the participants tested positive for microalbuminuria, less than 4% of these persons had ever been told they had kidney disease.
Lack of confirmatory testing with a serum creatinine (and estimated glomerular filtration rate) or, alternatively, with a 24-hour urine collection for creatinine clearance and protein excretion; no standardized follow-up for screened participants.
The KEOP targeted screenings disclosed a high prevalence of known risk factors for CKD--diabetes mellitus, hypertension, obesity, advanced age, and family history of kidney disease. However, despite these factors, less than 4% of screened participants were aware of a diagnosis of CKD.
North Carolina medical journal 70(6):507-12.
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ABSTRACT: Chronic kidney disease (CKD) and its progression to end-stage kidney disease (ESKD), requiring lifelong dialysis or kidney transplant, has become a public health epidemic and a financial burden on healthcare systems. The lack of available and appropriately targeted kidney disease education may account for the low awareness of kidney disease, especially among high risk populations. This low awareness can lead to late detection of CKD and an increased likelihood of progression to ESKD. This study utilized focus groups to assess community perceptions of kidney disease, barriers to health care, and educational interventions.
Seventeen focus groups were conducted with 201 participants in 5 rural North Carolina counties to assess perceptions of kidney disease, barriers to health care and strategies for raising awareness. Qualitative data analysis was performed based on a grounded theory approach.
Of the 201 participants, 74% were African-American, 96% knew someone with diabetes or hypertension, and 76% of groups contained at least one participant with a family member or friend diagnosed with ESKD. Participants were aware that kidneys acted as filters and mechanisms to cleanse the blood, and stated that alcohol, soda, obesity, diet, and urination problems were risk factors for developing CKD. Participants consistently mentioned that symptoms and risk factors for CKD were key pieces of knowledge. Affordability of health services, medicine, and insurance was seen as the biggest barrier to health care in the communities studied; knowing how to better communicate with physicians was also important. Television and word-of-mouth were mentioned most often as the best tools for outreach and education. Wal-Mart (a chain of large, discount department and grocery stores) and community churches were most commonly mentioned as potential places for screenings.
Results indicate that there is some basic community knowledge about kidney disease but the risk of developing kidney disease is often directly attributed to lifestyle behaviors rather than diabetes, hypertension, or cardiovascular disease. Future educational interventions need to be focused on the risk factors for kidney disease, and must address financial and geographic barriers to health care and poor communication between consumers and healthcare professionals.
Rural and remote health 10(2):1388. · 0.98 Impact Factor
