Clinical validation of immunoglobulin A nephropathy diagnosis in Swedish biopsy registers.

AIMS: The aims of this study were to validate the diagnosis of IgA nephropathy (IgAN) in Swedish biopsy registers against patient charts and to describe the clinical characteristics of patients with a biopsy indicating IgAN. METHODS: This is a population-based cohort study. Out of 4,069 individuals with a renal biopsy consistent with IgAN (biopsies performed in 1974-2011), this study reviewed patient charts of a random subset of 127 individuals. Clinical and biopsy characteristics at the time of biopsy were evaluated, and positive predictive values (PPV) were calculated with 95% confidence intervals (CI). RESULTS: Out of 127 individuals with a renal biopsy consistent with IgAN, 121 had a likely or confirmed clinical diagnosis of IgAN, primary or secondary to Henoch-Schönlein purpura, yielding a PPV of 95% (95% CI =92%-99%). The median age at biopsy was 39 years (range: 4-79 years); seven patients (6%) were <16 years. The male to female ratio was 2.8:1. The most common causes for consultation were macroscopic hematuria (n=37; 29%), screening (n=33; 26%), and purpura (n=14, 11%). In patients with available data, the median creatinine level was 104 µmol/L (range 26-986 µmol/L, n=110) and glomerular filtration rate 75 mL/min/1.73m2 (range 5-173 mL/min/1.73m2, n=114). Hypertension was noted in 59 (46%) individuals. IgA deposits were reported in 97% of the biopsy records (n=123), mesangial hypercellularity in 76% (n=96), C3 deposits in 89% (n=113), and C1q deposits in 12% (n=15). CONCLUSION: A histologic diagnosis of IgAN has a high PPV for a diagnosis of IgAN confirmed by review of patient charts.

Natural fluoride in drinking water and myocardial infarction: A cohort study in Sweden.

Large geographical variation in the coronary heart disease (CHD) incidence is seen worldwide and only a part of this difference is attributed to the classic risk factors. Several environmental factors, such as trace elements in the drinking water have been implicated in the pathogenesis of CHD. The objective was to assess the association between drinking water fluoride exposure and myocardial infarction in Sweden using nationwide registers. This large cohort consisted of 455,619 individuals, born in Sweden between January 1, 1900 and December 31, 1919, alive and living in their municipality of birth at the time of start of follow-up. Estimated individual drinking water fluoride exposure was stratified into four categories: very low (<0.3mg/l), low (0.3-<0.7mg/l), medium (0.7-<1.5mg/l) and high (≥1.5mg/l). In Cox regression analyses, compared to the very low fluoride group, the adjusted Hazard Ratio for the low fluoride group was 0.99 (95% confidence interval, 0.98-1.00), for the medium fluoride group 1.01 (95% confidence interval, 0.99-1.03) and 0.98 (95% confidence interval, 0.96-1.01) for the highest fluoride group. Adding water hardness to the model did not change the results. We conclude that the investigated levels of natural drinking water fluoride content does not appear to be associated with myocardial infarction, nor related to the geographic myocardial infarction risk variation in Sweden. Potential misclassification of exposure and unmeasured confounding may have influenced the results.

Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?

OBJECTIVE: To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions. METHODS: By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received. RESULTS: During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed. CONCLUSION: During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

Atrial vs. dual-chamber cardiac pacing in sinus node disease: a register-based cohort study.

AIMS: In patients with sinus node disease, dual-chamber pacing (DDD) possibly results in adverse effects on the ventricular function. We have compared the incidence of cardiovascular morbidity and mortality in patients with sinus node disease and with atrioventricular (AV) synchronous pacemakers, DDD vs. atrial pacing (AAI). METHODS AND RESULTS: A nation-wide population-based cohort of 8777 patients with AAI- or DDD-mode pacemakers was followed during 12 years. The cohort was linked to national healthcare and census registers. Patients with DDD pacing and without any pre-implant admission for atrial fibrillation or flutter had an increased risk of post-implant fibrillation or flutter, in relation to corresponding AAA patients [hazard ratio (HR) = 1.30; 95% confidence interval (CI) 1.10-1.52]. A slight increase in the risk of any cardiovascular disease (HR = 1.07; CI, 1.00-1.15), and all-cause mortality (HR = 1.12; CI, 1.00-1.25), was seen among DDD patients, in relation to AAI patients, but there was no significant difference in the risk of ischaemic or unspecified stroke (HR = 1.14; CI, 0.94-1.37). Among DDD patients, the all-cause mortality did not differ from the general population [standardized mortality ratio (SMR) = 1.04; CI, 0.98-1.11]. Patients with AAI, however, had a decreased all-cause mortality risk (SMR = 0.89; CI, 0.82-0.97). CONCLUSION: Our results support AAI as the preferred mode of pacing in patients with sinus node disease, and a normal AV node function.

Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists.

OBJECTIVES: The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was performed using prospectively collected data from the Swedish Biologics Register (ARTIS) and other national Swedish registers. METHODS: First, in the ARTIS, all 4167 rheumatoid arthritis (RA) patients starting TNF antagonist treatment between 1999 and 2003 were identified. Secondly, in the Swedish Inpatient Register, all individuals hospitalised for any reason and who also carried a diagnosis of RA, between 1964 and 2003 (n = 44 946 of whom 2692 also occurred in ARTIS), were identified. Thirdly, in the Swedish Inpatient Register, all hospitalisations listing an infection between 1999 and 2003 were identified. By cross-referencing these three data sets, RRs for hospitalisation with infection associated with TNF antagonist treatment were calculated within the cohort of 44 946 RA patients, using Cox regression taking sex, age, geography, co-morbidity and use of inpatient care into account. RESULTS: Among the 4167 patients treated with TNF antagonists, 367 hospitalisations with infections occurred during 7776 person-years. Within the cohort of 44 496 RA patients, the RR for infection associated with TNF antagonists was 1.43 (95% CI 1.18 to 1.73) during the first year of treatment, 1.15 (95% CI 0.88 to 1.51) during the second year of treatment, and 0.82 (95% CI 0.62 to 1.08) for subjects remaining on their first TNF antagonist treatment after 2 years. CONCLUSION: Treatment with TNF antagonists may be associated with a small to moderate increase in risk of hospitalisation with infection, which disappears with increasing treatment duration.

Obesity and risk for chronic renal failure.

Few large-scale epidemiologic studies have quantified the possible link between obesity and chronic renal failure (CRF). This study analyzed anthropometric data from a nationwide, population-based, case-control study of incident, moderately severe CRF. Eligible as cases were all native Swedes who were aged 18 to 74 yr and had CRF and whose serum creatinine for the first time and permanently exceeded 3.4 mg/dl (men) or 2.8 mg/dl (women) during the study period. A total of 926 case patients and 998 control subjects, randomly drawn from the study base, were enrolled. Face-to-face interviews, supplemented with self-administered questionnaires, provided information about anthropometric measures and other lifestyle factors. Logistic regression models with adjustments for several co-factors estimated the relative risk for CRF in relation to body mass index (BMI). Overweight (BMI>or=25 kg/m2) at age 20 was associated with a significant three-fold excess risk for CRF, relative to BMI<25. Obesity (BMI>or=30) among men and morbid obesity (BMI>or=35) among women anytime during lifetime was linked to three- to four-fold increases in risk. The strongest association was with diabetic nephropathy, but two- to three-fold risk elevations were observed for all major subtypes of CRF. Analyses that were confined to strata without hypertension or diabetes revealed a three-fold increased risk among patients who were overweight at age 20, whereas the two-fold observed risk elevation among those who had a highest lifetime BMI of >35 was statistically nonsignificant. Obesity seems to be an important-and potentially preventable-risk factor for CRF. Although hypertension and type 2 diabetes are important mediators, additional pathways also may exist.

Cholecystectomy in Sweden 1987-99: a nationwide study of mortality and preoperative admissions.

OBJECTIVE: Information on mortality after cholecystectomy in defined populations is limited. In this study we examined the case fatality rates and mortality ratios, based on register data. MATERIAL AND METHODS: Hospital discharge and death certificate data were linked for all patients undergoing cholecystectomy in Sweden in 1987-99. Mortality risk was calculated as the standardized mortality ratio (SMR). RESULTS: From 1 January 1987 to 1 December 1999, 123,099 patients underwent cholecystectomy for acute or chronic gallbladder disease. Between 1987-91 and 1995-99, the incidence of cholecystectomy increased by 13%, median age of patients decreased and the proportion of women increased. From 1995 to 1999, 32% of all cholecystectomies were completed as open cholecystectomy. During this period, 82% of patients aged 70 years or older with acute gallstone disease had an open cholecystectomy. For patients with chronic gallstone disease, the proportion was 43%. Postoperative crude mortality within 30 days for all patients was 0.4%. Patients with acalculous gallbladder disease had double the mortality risk compared with patients with calculous disease, and patients with acute cholecystitis had double the risk compared with patients with chronic disease. High age, previous hospital admission for conditions other than gallbladder disease, and cholecystectomy completed as an open procedure increased the risk, whereas gender and calendar year did not significantly affect the mortality risk. Biliary tract diseases accounted for 61% of all postoperative deaths, whereas 26% were due to cardiovascular diseases. CONCLUSIONS: During the 1990s, cholecystectomy incidence increased, whereas postoperative mortality risk remained unchanged. In order to further reduce the mortality risk, particular attention should be paid to elderly and frail patients and to patients with acalculous gallbladder disease.

The natural history of chronic renal failure: results from an unselected, population-based, inception cohort in Sweden.

BACKGROUND: Mortality rates in patients with chronic renal failure (CRF) are high both before and after start of renal replacement therapy (RRT). However, few studies of mortality and progression have been performed in an unselected CRF population. METHODS: We followed up a population-based inception cohort of 920 men and women aged 18 to 74 years who had CRF (serum creatinine level > 3.4 mg/dL [>300 micromol/L] for men and >2.8 mg/dL [>250 micromol/L] for women) for 55 to 79 months. Relationships between the outcomes (death and start of RRT) and independent variables under study (age, sex, primary renal disease, body mass index [BMI], and glomerular filtration rate [GFR] at entry) were explored by using Cox regression models. RESULTS: Seven hundred thirty-nine patients (80%) started RRT during the follow-up period. As expected, GFR at entry was clearly linked to the incidence of RRT (P < 0.0001). Age was related inversely to incidence of RRT (adjusted relative risk for patients > or =65 years relative to patients <45 years, 0.72; 95% confidence interval, 0.57 to 0.90). Men progressed to RRT more often than women (adjusted relative risk, 1.59; 95% confidence interval, 1.35 to 1.88). BMI was unrelated to RRT incidence. By the end of follow-up, 389 patients with CRF (42%) had died, 89 of them (10%) before the start of RRT. The most common primary cause of death was cardiovascular disease (37.5%). Characteristics significantly related to a greater mortality rate included older age, diagnoses of diabetic nephropathy and nephrosclerosis, and low BMI. CONCLUSION: Preuremic characteristics (age, sex, primary renal diagnosis, BMI, and GFR) are predictive of prognosis in unselected patients with CRF.

Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden.

OBJECTIVE: Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA. METHODS: Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004. RESULTS: During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment. CONCLUSION: Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.

Association between smoking and chronic renal failure in a nationwide population-based case-control study.

For determining whether smoking is associated with an increased risk for chronic renal failure (CRF) overall and by type of renal disease, smoking data were analyzed from a nationwide population-based case-control study. Eligible as cases were native 18- to 74-yr-old Swedes whose serum creatinine for the first time and permanently exceeded 3.4 mg/dl (men) or 2.8 mg/dl (women). A total of 926 cases (78% of all eligible) and 998 control subjects (75% of 1330 randomly selected subjects from the source population), frequency matched to the cases by gender and age within 10 yr, were included. A face-to-face interview and a self-administered questionnaire provided information about smoking habits and other lifestyle factors. Logistic regression models estimated odds ratios (OR) as measures of relative risk for disease-specific types of CRF among smokers compared with never-smokers. Despite a modest and nonsignificant overall association, the risk increased with high daily doses (OR among smokers of >20 cigarettes/d, 1.51; 95% confidence interval [CI], 1.06 to 2.15), long duration (OR among smokers for >40 yr, 1.45; 95% CI, 1.00 to 2.09), and a high cumulative dose (OR among smokers with >30 pack-years, 1.52; 95% CI, 1.08 to 2.14). Smoking increased risk most strongly for CRF classified as nephrosclerosis (OR among smokers with >20 pack-years, 2.2; 95% CI, 1.3 to 3.8), but significant positive associations were also noted with glomerulonephritis. This study thus suggests that heavy cigarette smoking increases the risk of CRF for both men and women, at least CRF classified as nephrosclerosis and glomerulonephritis.

Absence of association between organic solvent exposure and risk of chronic renal failure: a nationwide population-based case-control study.

Exposure to organic solvents has been suggested to cause or exacerbate renal disease, but methodologic concerns regarding previous studies preclude firm conclusions. We examined the role of organic solvents in a population-based case-control study of early-stage chronic renal failure (CRF). All native Swedish residents aged 18 to 74 yr, living in Sweden between May 1996 and May 1998, formed the source population. Incident cases of CRF in a pre-uremic stage (n = 926) and control subjects (n = 998), randomly selected from the study base, underwent personal interviews that included a detailed occupational history. Expert rating by a certified occupational hygienist was used to assess organic solvent exposure intensity and duration. Relative risks were estimated by odds ratios (OR) in logistic regression models, with adjustment for potentially important covariates. The overall risk for CRF among subjects ever exposed to organic solvents was virtually identical to that among never-exposed (OR, 1.01; 95% confidence interval [CI], 0.81 to 1.25). No dose-response relationships were observed for lifetime cumulative solvent exposure, average dose, or exposure frequency or duration. The absence of association pertained to all subgroups of CRF: glomerulonephritis (OR, 0.96; 95% CI, 0.68 to 1.34), diabetic nephropathy (OR, 1.02; 95% CI, 0.74 to 1.41), renal vascular disease (OR, 1.16; 95% CI, 0.76 to 1.75), and other renal CRF (OR, 0.92; 95% CI, 0.66 to 1.27). The results from a nationwide, population-based study do not support the hypothesis of an adverse effect of organic solvents on CRF development, in general. Detrimental effects from subclasses of solvents or on specific renal diseases cannot be ruled out.

Socio-economic status and chronic renal failure: a population-based case-control study in Sweden.

BACKGROUND: Low socio-economic status is associated with the occurrence of several different chronic diseases, but evidence regarding renal disease is scant. To explore whether the risk of chronic renal failure varies by socio-economic status, we performed a population-based case-control study in Sweden. METHODS: All native residents from May 1996 to May 1998, aged 18-74 years, formed the source population. Cases (n = 926) were incident patients with chronic renal failure in a pre-uraemic stage. Control subjects (n = 998) were randomly selected within the source population. Exposures were assessed at personal interviews and relative risks were estimated by odds ratios (OR) in logistic regression models, with adjustment for age, sex, body mass index (BMI), smoking, alcohol consumption and regular analgesics use. RESULTS: In families with unskilled workers only, the risk of chronic renal failure was increased by 110% [OR = 2.1; 95% confidence interval (CI), 1.1-4.0] and 60% (OR = 1.6; 95% CI, 1.0-2.6) among women and men, respectively, relative to subjects living in families in which at least one member was a professional. Subjects with 9 years or less of schooling had a 30% (OR = 1.3; 95% CI, 1.0-1.7) higher risk compared with those with a university education. The excess risk was of similar magnitude regardless of underlying renal disease. CONCLUSIONS: Low socio-economic status is associated with an increased risk of chronic renal failure. The moderate excess was not explained by age, sex, BMI, smoking, alcohol or analgesic intake. Thus, socio-economic status appears to be an independent risk indicator for chronic renal failure in Sweden.