Traditional and Disease-Specific Risk Factors for Cardiovascular Events in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Multinational Retrospective Study.

OBJECTIVE: To investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA. METHODS: Patients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Over a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs. CONCLUSION: We showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV.

Rituximab in Membranous Nephropathy.

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of "the new standard."

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

OBJECTIVE: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. METHODS: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. CONCLUSION: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown?

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.

Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Background: In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods: Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results: A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions: The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.

Serum C3 complement levels in ANCA associated vasculitis at diagnosis is a predictor of patient and renal outcome.

AIM: To determinate the prognostic significance of low serum C3 at the time of diagnosis of ANCA-associated vasculitis (AAV). METHODS: Our cohort included 75 consecutive patients with AAV diagnosed from January 2005 to December 2015. C3 levels were measured at the time of diagnosis. Patients were divided into two groups, those with low serum C3 levels (< 0.9 g/l) and those with normal serum C3 levels (0.9-1.8 g/l). We analysed association between serum C3 levels and both combined and singularly patient and renal survival (ESRD). Small number of relapsed patients did not allow for the statistical analysis to be performed as to weather the low serum C3 is associated with relapse rate in AAV patients. RESULTS: Low serum C3 levels were significantly associated with worse combined end-point patient and renal survival (HR 3.079; 95% CI 1.231-7.701; p = 0.016), and on multivariate adjusted analysis association remained significant (HR 2.831; 95% CI 1.093-7.338; p = 0.032). For both end-points individually low serum C3 levels were significantly associated with poorer patient survival (HR 6.378; 95% CI 2.252-18.065; p < 0.001; on multivariate adjusted analysis HR 4.315 95% CI 1.350-13.799; p = 0.014) and renal survival (HR 3.207; 95% CI 1.040-9.830; p = 0.043; on multivariate adjusted analysis HR 3.679; 95% CI 1.144-11.827; p = 0.029). In our study there was no significant association between serological and patohistological phenotypes and serum C3 levels. CONCLUSION: Lower serum C3 levels at the diagnosis is associated with poorer patient and renal outcomes in AAV patients.

Clinical, serological and histological determinants of patient and renal outcome in ANCA-associated vasculitis with renal involvement: an analysis from a referral centre.

PURPOSE: To evaluate significance of clinical and histopathological prognostic factors for renal and patient outcome in AAV patient cohort. METHODS: Retrospective study included consecutive patients diagnosed with pauci-immune crescentic glomerulonephritis from January 2003 to December 2013. Primary outcome was combined endpoint patient death or progression to end-stage renal disease (ESRD). Secondary outcomes were patient survival and progression to ESRD (renal survival) singularly and disease relapse. Kaplan-Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between phenotypes and finding significant predictors regarding outcomes. RESULTS: Out of 81 patients, 40.7% patients reached primary endpoint, 22.2% died, 29.6% reached ESRD and 16% relapsed during follow-up. Multivariate Cox proportional hazards regression-adjusted analysis found higher BVAS (HR 1.08, 95% CI 1.01-1.17, p = 0.042), higher baseline maximal serum creatinine (HR 1.02, 95% CI 1.01-1.03, p = 0.04) and lower haemoglobin (HR 0.97, 95% CI 0.95-0.99, p = 0.011) significantly associated with primary endpoint. Higher BVAS (HR 1.25, 95% CI 1.01-1.43, p = 0.001) and lower haemoglobin (HR 0.95, 95% CI 0.91-0.99, p = 0.008) were significantly associated with patient survival, while for renal survival, lower haemoglobin (HR 0.97, 95% CI 0.94-0.99, p = 0.041) and the need for acute haemodialysis (HR 3.15, 95% CI 1.20-8.26, p = 0.02) were significant predictors. On multivariate-adjusted analysis, no significant predictors for disease relapse were found. Kaplan-Meier survival analysis found no difference between clinical, serological and pathohistological phenotypes for all of the endpoints. CONCLUSIONS: Renal function at presentation, anaemia and BVAS should be included in prediction models for the outcomes for the AAV patients.

[HYPOKALEMIC METABOLIC ALKALOSIS ­ A REPORT OF SIX CASES].

In this article six patients with hypokalemic metabolic alkalosis, classified as Bartter or Gitelman syndrome are presented. Both syndromes result from different gene mutation inducing impaired function of the transporters involved in sodium, chloride and potassium reapsorption in thick ascending limb of the loop of Henle and distal convoluted tubules. These syndromes typically present with hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism without hypertension, polyuria and muscle weakness. Other clinical characteristics may vary considerably, depending on the gene expression. Correct diagnosis is only possible using expensive and not-routinely available genetic testing. Routine laboratory tests, especially those considering serum and urine electrolytes, can help in recognizing these syndromes and therefore in timely beginning of treatment. The most important distinctive laboratory findings are serum magnesium concentration and urine calcium excretion. In Bartter syndrome typically there is hypercalciuria with or without hypomagnesemia, while in Gitelman syndrome typical findings are hypocalciuria and hypomagnesemia. Recognizing and treating these patients is important due to possible increased morbidity and mortality induced by severe electrolyte imbalance.

Cardiac surgery-associated acute kidney injury: risk factors analysis and comparison of prediction models.

OBJECTIVES: Cardiac surgery-associated acute kidney injury (AKI) is a well-known factor influencing patients' long-term morbidity and mortality. Several prediction models of AKI requiring dialysis (AKI-D) have been developed. Only a few direct comparisons of these models have been done. Recently, a new, more uniform and objective definition of AKI has been proposed [Kidney Disease: Improve Global Outcomes (KDIGO)-AKI]. The performance of these prediction models has not yet been tested. METHODS: Preoperative demographic and clinical characteristics of 1056 consecutive adult patients undergoing cardiac surgery were collected retrospectively for the period 2012-2014. Multivariable logistic regression analysis was used to determine the independent predictors of AKI-D and the KDIGO-AKI stages. Risk scores of five prediction models were calculated using corresponding subgroups of patients. The discrimination of these models was calculated by the c-statistics (area under curve, AUC) and the calibration was evaluated for the model with the highest AUC by calibration plots. RESULTS: The incidence of AKI-D was 3.5% and for KDIGO-AKI 23% (17.3% for Stage 1, 2.1% for Stage 2 and 3.6% for Stage 3). Older age, atrial fibrillation, NYHA class III or IV heart failure, previous cardiac surgery, higher preoperative serum creatinine and endocarditis were independently associated with the development of AKI-D. For KDIGO-AKI, higher body mass index, older age, female gender, chronic obstructive pulmonary disease, previous cardiac surgery, atrial fibrillation, NYHA class III or IV heart failure, higher preoperative serum creatinine and the use of cardiopulmonary bypass were independent predictors. The model by Thakar et al. showed the best performance in the prediction of AKI-D (AUC 0.837; 95% CI = 0.810-0.862) and also in the prediction of KDIGO-AKI stage 1 and higher (AUC = 0.731; 95% CI = 0.639-0.761), KDIGO-AKI stage 2 and higher (AUC = 0.811; 95% CI = 0.783-0.838) and for KDIGO-AKI stage 3 (AUC = 0.842; 95% CI = 0.816-0.867). CONCLUSIONS: The performance of known prediction models for AKI-D was found reasonably well in the prediction of KDIGO-AKI, with the model by Thakar having the highest predictive value in the discrimination of patients with risk for all KDIGO-AKI stages.

Tetralogy of Fallot with cor triatriatum dexter in an adult patient: a case report.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect with only approximately 3% of uncorrected patients surviving past age 40. In this case report, we present a 48-year-old mentally retarded man suffering from congenital spastic quadriplegia who was diagnosed with a unique combination of symptomatic TOF and cor triatriatum dexter (CTD). Reduced preload because of CTD with spastic quadriplegia that prevented physical exertion is believed to have facilitated this patient's unusually long survival.