Hyunsook Chin

Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody–Associated Small-Vessel Vasculitis

Context Patients with antineutrophil cytoplasmic autoantibody (ANCA)associated small-vessel vasculitis sometimes experience relapses and resistance to glucocorticoid and cyclophosphamide treatment. Contribution This study followed 350 patients with ANCA-associated vasculitis for a median of 49 months. Of 258 patients attaining remission, 109 (42%) relapsed. Upper or lower respiratory tract disease and proteinase-3 ANCA seropositivity were associated with increased risk for relapse. Of 334 treated patients, 77 (23%) had progressive disease despite treatment. Severe kidney disease, black ethnicity, and female sex were associated with an increased risk for treatment resistance. Cautions The participants were primarily selected on the basis of their condition being identified by renal biopsy. The Editors Antineutrophil cytoplasmic antibody (ANCA)associated small-vessel vasculitis includes microscopic polyangiitis, Wegener granulomatosis, the ChurgStrauss syndrome, and renal-limited vasculitis (ANCA-associated glomerulonephritis) (1, 2). The cornerstone of treatment for ANCA-associated vasculitis includes induction therapy with pulse corticosteroids and the prompt institution of daily oral glucocorticoids and cyclophosphamide (3-6). Approximately 85% of patients achieve remission with this therapy (5), but 11% to 57% of patients have a relapse (7-11). Some relapses are severe, resulting in worsening end-organ damage. Most relapses respond to therapy, but patients are subjected to additional immunosuppressive or cytotoxic drugs. Fear of relapsing disease has impelled physicians to prescribe prolonged maintenance therapies in most patients. Because 43% to 89% of patients may never have a disease relapse (7-11), use of long-term immunomodulating therapy often presents unnecessary risks and may well outweigh the benefits of preventing relapse. Little is known regarding predictors for relapse; identification of these risk factors would conceivably allow maintenance immunomodulatory therapy to be tailored to patients at high risk while sparing others unnecessary exposure to these drugs. Over the course of almost 2 decades, we recruited a large cohort of patients with ANCA-associated glomerulonephritis and vasculitis. From this sample, we sought to ascertain the following: Which patients were more likely to be resistant to treatment; which patients were more likely to progress to end-stage kidney disease; the potential to determine which patients were more likely to relapse; the impact of relapse on long-term outcome; the correlation between length of immunosuppressive therapy and the likelihood of relapse; and the viability of discontinuing immunosuppressive therapy in patients who have attained remission. Methods Patient Sample and Definitions Patients were eligible for this study if they had biopsy-proven vasculitis (diagnosed between 1985 and 2003) with positive ANCA determination by immunofluorescence microscopy or antigen-specific enzyme-linked immunosorbent assay (12); the patients were also required to be followed by physicians of the Glomerular Disease Collaborative Network (GDCN). The GDCN and a subset of the cohort were previously described elsewhere (4, 7), but the cohort was expanded to evaluate predictors of relapse. We used the University of North Carolina (UNC) Nephropathology Laboratory, which evaluates more than 1500 renal biopsies each year, to recruit participants for the GDCNs registry of patients with ANCA-associated vasculitis. All patients with a native kidney biopsy diagnosis of pauci-immune necrotizing and crescentic glomerulonephritis with or without granulomatous inflammation were eligible to enroll in the registry (n= 639). Patients were invited to give informed consent to participate through their treating nephrologist. We then collected medical records dating back to the initial diagnosis of ANCA-associated vasculitis. A total of 307 patients (48% of eligible participants) with a biopsy-proven diagnosis were enrolled in this study. An additional 59 (9%) patients signed consent to participate but were deemed ineligible because of negative ANCA test results or overlapping disease. Another 43 patients who had not undergone renal biopsy were recruited through the multidisciplinary UNC Vasculitis Clinic and through other GDCN nephrologists who work in collaboration with other medical specialists to care for patients with ANCA-associated vasculitis. Estimates of potentially eligible patients without a kidney biopsyproven diagnosis were not available because no centralized service exists to evaluate nonrenal biopsy tissue. Initial biopsy diagnosis, whatever the organ, was used as each patients start date in the registry. Detailed information on duration of symptoms before biopsy diagnosis was not always described in medical records and therefore was not available for analysis in this study. The Committee on the Protection of Human Subjects at UNC approved this study. Patients in the cohort received clinically indicated care from their primary nephrologists, who were affiliated with 63 different GDCN private practice offices (1 to 12 nephrologists per office) and 5 academic medical centers, including UNC. Therapeutic interventions and frequency of clinical evaluations were not determined by protocol. Physicians were instructed to update GDCN records for patients on a yearly basis; follow-up calls and written reminders were provided if information was not received. Consequently, patient follow-up did not vary substantially across clinics. Patients were categorized as having cytoplasmic ANCA, antiproteinase-3 (anti-PR3) ANCA, or both, or perinuclear ANCA, anti-myeloperoxidase (anti-MPO) ANCA, or both. Patients having only perinuclear ANCA were required to have a negative antinuclear antibody test. Categories of ANCA-associated vasculitis included Wegener granulomatosis, microscopic polyangiitis, and renal-limited disease (1, 2). The single patient with the ChurgStrauss syndrome was included with the microscopic polyangiitis group. Organ involvement was determined by biopsy or by previously described criteria (4, 7). For example, lung involvement was considered likely in the presence of hemoptysis; pulmonary hemorrhage; respiratory failure; or radiographic proof of infiltrates, nodules, or cavities without evidence of infection. Upper respiratory tract disease was considered likely with clinical or radiographic studies revealing sinusitis, otitis media, nasal crusting, or subglottic disease. Treatment categories were determined by the first therapy regimen used at diagnosis (corticosteroids alone or in combination with cyclophosphamide, as previously described) (3). In brief, induction therapy was typically initiated with 3 daily pulses of methylprednisolone (7 mg/kg of body weight per day) followed by daily oral prednisone. Prednisone therapy was started at a dose of 1 mg/kg per day for the first month and was tapered over 3 to 4 months. Cyclophosphamide was administered by intravenous pulse (0.5 to 1 g/m2 per month) or orally (1 to 2 mg/kg per day). Other immunosuppressive regimens included azathioprine, mycophenolate mofetil, and cyclosporine, usually after completion of induction therapy. The duration of therapy with various immunosuppressive medications was recorded. Patients were considered to be treated if they received any immunosuppressive therapy, regardless of duration. Medical records were reviewed on an ongoing basis. Drs. Falk and Nachman determined the outcomes, which included treatment resistance, remission while receiving therapy, remission without therapy, relapse, and end-stage kidney disease (4, 7). Treatment resistance was defined as progressive decline in kidney function with persistence of active urine sediment, or new or persisting extrarenal manifestations of vasculitis despite immunosuppressive therapy. Resistance to therapy was determined at least 1 month after the start of treatment. Remission was defined as stabilization or improvement of kidney function as measured by serum creatinine levels and resolution of hematuria and other manifestations of systemic vasculitis for more than 1 month. Remission without therapy was defined as remission while receiving only 7.5 mg of corticosteroids per day or less. Relapse could only occur in patients who reached remission (with or without therapy). Relapse was defined as vasculitic signs or symptoms in any organ system, as previously described (4, 7). Histopathologic renal evaluations included assessment of disease activity, chronicity, and vascular sclerosis. Scores ranging from 0 to 4 were used to designate degrees of glomerular necrosis, cellular crescents, neutrophil infiltration, capillary wall thickening, glomerular hypercellularity, and interstitial leukocytes; the sum of these scores was used to grade overall renal activity (range, 0 to 24). Chronicity was quantified by the sum of the scores (0 to 4 for each) for glomerular sclerosis, fibrotic crescents, interstitial fibrosis, and tubular atrophy (range, 0 to 16). Vascular sclerosis was scored from 0 to 4. The 4-variable Modification of Diet in Renal Disease equation (13, 14) was used to estimate glomerular filtration rate (GFR). Improvement or decline in GFR of 8 mL/min or more over 4 months was considered a clinically significant change in renal function. Statistical Analyses Logistic regression was used to assess factors associated with treatment resistance. A time-to-event analysis was not used because actual time to resistance is not known and because outcomes occurred within a short time. Results were expressed as odds ratios with 95% CIs. KaplanMeier estimators were used to estimate median survival times and probability of survival without end-stage kidney disease (15, 16). Cause-specific proportional hazards models were used to study, as competing risks, the 2 mutually exclusive outcomes of time to relapse (active disease outcome) and time to end-stage kidney disease

Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody–associated small‐vessel vasculitis: Comparison of two independent cohorts

OBJECTIVE Predictors of treatment resistance and relapse have been identified in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the Glomerular Disease Collaborative Network (GDCN) in the southeastern US. This study was undertaken to evaluate the applicability of those predictors in an independent cohort followed up by the French Vasculitis Study Group. METHODS Predictors of treatment resistance were evaluated using logistic regression models and reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). Predictors of relapse were evaluated using Cox proportional hazards models and reported as hazard ratios (HRs) with 95% CIs. Models were controlled for age, sex, race, baseline serum creatinine level, and cyclophosphamide therapy. RESULTS The French cohort (n = 434) and the GDCN cohort (n = 350) had similar median followup periods (44 months versus 45 months) and initial percentages of patients taking cyclophosphamide (82% versus 78%). The French cohort included more patients with proteinase 3 (PR3) ANCA (58% versus 40%), lung involvement (58% versus 49%), and upper respiratory tract involvement (62% versus 31%). Of the predictors of treatment resistance in the GDCN cohort (female sex, African American race, presence of myeloperoxidase ANCA, elevated creatinine level, and age), only age predicted treatment resistance in the French cohort (OR 1.32 per 10 years [95% CI 1.05-1.66]). Predictors of relapse in the GDCN cohort were PR3 ANCA (HR 1.77 [95% CI 1.11-2.82]), lung involvement (HR 1.68 [95% CI 1.10-2.57), and upper respiratory tract involvement (HR 1.58 [95% CI 1.00-2.48]), while predictors in the French cohort were PR3 ANCA (HR 1.66 [95% CI 1.15-2.39]) and lung involvement (HR 1.56 [95% CI 1.11-2.20]), but not upper respiratory tract involvement (HR 0.96 [95% CI 0.67-1.38]). CONCLUSION Our findings indicate that older age is a predictor of treatment resistance, and that PR3 ANCA and lung involvement are predictors of relapse in both cohorts. Discrepancies in predictors of treatment tract resistance may reflect differences in access to care, and differences in predictors of relapse may reflect variations in disease expression.

Association of Silica Exposure with Anti–Neutrophil Cytoplasmic Autoantibody Small-Vessel Vasculitis: A Population-Based, Case-Control Study

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.

Obesity, Albuminuria, and Urinalysis Findings in US Young Adults from the Add Health Wave III Study

BACKGROUND AND OBJECTIVES Obesity has been associated with kidney disease in adults. This study was designed to evaluate the association of obesity with an early marker of kidney disease, albuminuria, among young adults. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Urinalysis (n = 9371), albumin-to-creatinine ratio (n = 4463), and body mass index (kg/m2) were measured in the Add Health Wave III cohort (2001 to 2002), a multiethnic sample of young adults followed for approximately 6 yr. Multivariate logistic regression modeled the association of sex-specific albuminuria with body mass index, adjusted for sample weights, sex, race, ethnicity, and glycosuria. RESULTS Urinalysis revealed that 0.8% had proteinuria, 4.6% had hematuria, 0.2% had combined hematuria and proteinuria, and 1.5% had glycosuria. Albuminuria prevalence was 4.4%. Mean body mass index was higher among those with albuminuria compared with those without. There were no associations between body mass index categories of 25 to < 30 or 30 to < 35 kg/m2 with albuminuria compared with the lowest body mass index (< 25 kg/m2); however, the highest category (> or = 35 kg/m2) was associated with albuminuria, compared with the lowest category (OR = 1.76, 95% CI: 1.02 to 3.04). Glycosuria (OR = 4.0; 95% CI: 1.5 to 11.1, p < 0.01) as well as increasing body mass index during the 6-yr follow-up (OR: 1.07 per unit change in kg/m2; 95% CI: 1.00 to 1.13, p = 0.04) were also associated with albuminuria. CONCLUSIONS Given the increasing prevalence of obesity, the association of albuminuria associated with obesity in young adults is particularly concerning. Obesity may be a target for primary prevention of kidney and cardiovascular disease.

Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua

Background and objectives: Endemic renal insufficiency (RI) of unknown etiology is a major public health issue with high mortality in the Pacific coastal regions of Central America. We studied RI in León and Chinandega, Nicaragua, evaluating associations with known risk factors and hypothesized exposures. Methods: A cross-sectional survey was conducted with assessment of medical, social, and occupational history and exposures in conjunction with measurement of serum creatinine. Cases were defined by an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 using the modified four-variable Modification of Diet in Renal Disease (MDRD) study equation for non-African Americans. Logistic regression models controlling for known risk factors of kidney disease were used to evaluate associations between exposures and RI. Results: A total of 124 RI cases were compared to 873 persons without RI. Cases had no significant differences in the odds of having a systolic blood pressure (SBP) > 140 or diastolic blood pressure (DBP) > 90 mmHg, or in reporting diabetes. Agricultural labor was associated with RI (OR = 2.48, 95%CI: 1.59, 3.89, p < 0.0001). There was no association with agricultural non-field work (OR = 0.91, 95%CI: 0.60, 1.38, p = 0.65). Consumption of unregulated alcohol (“lija”) was associated with RI (OR = 2.10, 95%CI: 1.31, 3.39, p = 0.0023), as was drinking 5 L or more of water per day (OR = 3.59 vs. 1 L 95%CI: 1.52, 4.46, p = 0.0035). Conclusions: Agricultural field labor and lija consumption were associated with RI in this region. Water intake may also be important. Identifying specific risk factors for RI within these exposures, such as individual pesticides or lija ingredients, may facilitate prevention in a setting where dialysis and transplantation are limited.

ANCA patients have T cells responsive to complementary PR-3 antigen

Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3(138-169)-peptide; while only a third of the patients had HI-PR3 protein responsive T cells. A significant number of T cells from patients responded to cPR3(138-169) peptide and to HI-PR3 protein by proliferation and/or secretion of IFN-gamma, compared to healthy controls while there was no response to scrambled peptide. Cells responsive to cPR3(138-169)-peptide were not detected in MPO-ANCA patients suggesting that this response is specific. The HLADRB1(*) 15 allele was significantly overrepresented in our patient group and is predicted to bind cPR3(138-169) peptide with high affinity. Regression analysis showed a significant likelihood that anti-cPR3 antibodies and cPR3-specific T cells coexist in individuals, consistent with an immunological history of encounter with a PR3-complementary protein. We suggest that the presence of cells reacting to potential complementary protein pairs might provide an alternative mechanism for auto-immune diseases.

Effects of atorvastatin on low-density lipoprotein cholesterol phenotype and C-reactive protein levels in patients undergoing long-term dialysis.

Study Objectives. To determine the effects of atorvastatin on low‐density lipoprotein cholesterol (LDL) particle size and C‐reactive protein (CRP) concentrations in patients undergoing long‐term hemodialysis. Another objective was to compare the effects of atorvastatin on lipoprotein profiles as determined by direct versus indirect assessment of lipoprotein composition.

Reengineering clinical operations in a medical practice to optimize the management of anemia of chronic kidney disease.

Objectives. To describe the clinic design, clinical evaluations, and treatment approaches used in a multidisciplinary clinic for management of anemia of chronic kidney disease (CKD), and to evaluate several selected clinical outcomes associated with this approach to anemia management.

Predialysis chronic kidney disease: Evaluation of quality of life in clinic patients receiving comprehensive anemia care

BACKGROUND Anemia is common in chronic kidney disease (CKD), and suboptimal management of anemia can lead to serious health complications and poor quality of life (QOL). OBJECTIVES (1) To describe health-related and overall QOL among patients entering a clinic focused on anemia management; (2) to compare their baseline QOL with other relevant populations; (3) to explore predictors of QOL before anemia management; and (4) to explore changes in QOL over 1 year for patients managed in the clinic. METHODS The Kidney Disease Quality of Life questionnaire-short form (KDQOL-SF, Rand Corporation, Santa Monica, CA) was used to measure kidney disease specific and overall QOL in a cohort of predialysis CKD patients (n=79) enrolled in the clinic from January 2003 to September 2004. Baseline measures were compared to previously published measurements. The influence of demographic and clinical characteristics on baseline QOL was explored. Changes in QOL were evaluated over time. RESULTS Patients with CKD entering the clinic had lower overall QOL compared with estimates from the general U.S. population (physical composite 35.7 vs 48.4 and mental composite 46.0 vs 50.2, respectively). Clinic patients had better kidney disease-specific scores than patients with end-stage kidney disease (ESRD). General QOL scores were similar regardless of kidney disease severity, with the exception of physical functioning which was lowest for patients with end-stage disease. Hemoglobin was the only factor predictive of QOL. Over time, QOL improved among patients managed in the CKD clinic, with statistically significant improvements in sleep (change of 6.2+/-15.2; P<.05) and social function (change of 11.6+/-27.7; P<.05). CONCLUSIONS Patients with anemia of CKD reported reduced QOL compared to populations without kidney disease, but better QOL compared to populations with ESRD on dialysis. QOL generally improved among patients managed in the multidisciplinary anemia clinic.

Effects of Atorvastatin on Lp(a) and Lipoprotein Profiles in Hemodialysis Patients

Background: Dialysis patients have many underlying traditional and nontraditional risk factors that may predispose them to a high prevalence of cardiovascular disease. The effects of statins (eg, atorvastatin) on altering nontraditional lipoprotein measures in dialysis patients have not been extensively investigated. Objective: To evaluate the efficacy of atorvastatin compared with a control group in inducing changes in lipoprotein(a) [Lp(a)], apolipoprotein (Apo) A-1, Apo-B, and fibrinogen levels, as well as the conventional lipoprotein profile, in hemodialysis patients over 36 weeks; secondary objectives were to assess changes in C-reactive protein, albumin, and safety measures. Methods: Forty-five hemodialysis patients with low-density lipoprotein cholesterol (LDL-C) levels greater than 100 mg/dL were randomized to parallel groups: atorvastatin (n = 19) or no treatment (n = 26). The atorvastatin dose was titrated from 10 mg to achieve an LDL-C goal of 100 mg/dL or less and therapy was continued for 36 weeks. Biochemical and lipoprotein laboratory tests for efficacy outcomes were obtained at baseline, 12 weeks, and 36 weeks. Results: The atorvastatin group exhibited clinically significant reductions (mean ± SD) compared with controls in total cholesterol (–21.7 ± 41.7 vs –3.2 ± 40.0 mg/dL, respectively; p = 0.017) and LDL-C (–13.1 ± 32.0 vs –1.1 ± 38.4 mg/dL. respectively; p = 0.056) levels, as well as Lp(a) (–10.6 ± 27 vs 3.5 ± 17.8 mg/dL, respectively; p = 0.046). Statistical analyses included analysis of variance on ranked measures for multivariable modeling and paired t-test to determine changes in efficacy measures between baseline and 36 weeks within groups. Conclusions: Atorvastatin was safe and effective in reducing Lp(a), total cholesterol, and LDL-C levels. Given the prevalence of atherosclerosis in hemodialysis patients, therapy aimed at reducing traditional and nontraditional risk factors may be beneficial.