The elevation of the anion gap in steady state chronic kidney disease may be less prominent than generally accepted

BACKGROUND: A presumed cause of metabolic acidosis in chronic kidney disease (CKD) is accumulation of unmeasured anions, leading to a high anion gap (AG). In patients with CKD with a high AG, only minor increases are expected. The aim of this study is to evaluate the magnitude of the AG in documented steady state CKD to examine the effect of CKD on a high-AG metabolic acidosis (HAGMA).METHODS: In this cross-sectional study the AG, bicarbonate, and chloride were evaluated in 1045 blood and urine samples of 501 patients with steady state CKD in the outpatient clinic. The influence of phosphate, albumin and potassium on the AG were evaluated.RESULTS: The mean AG increased from 8.8 mEq/l (±1.57) in CKD stage 1 to 11.2 mEq/l (±2.22) in CKD stage 5 ( P &lt; 0.001). Correction for albumin or phosphate did not influence the magnitude of the AG. Correction for potassium did alter the prevalence of HAGMA, but not the severity. [HCO 3 -] decreased between CKD stages 1 and 5 by 5.1 mEq/l. The [Cl -] increased by 2.6 mEq/l between CKD stages 1 and 5. CONCLUSIONS: The elevation of the AG in patients with steady state CKD is limited and less pronounced than the decrease in [HCO 3 -]. Normal AG metabolic acidosis seems to be more important in CKD than HAGMA. The CKD stage and the magnitude of the AG should be taken into account when evaluating a patient with HAGMA. This study suggests that an AG &gt;15 mEq/l is rarely due to renal failure alone. </p

Oxalate nephropathy in an elderly patient with newly diagnosed celiac disease:a case report

Oxalate nephropathy, due to secondary hyperoxaluria has widely been described in gastrointestinal diseases. However, reports of oxalate nephropathy in newly diagnosed celiac disease are rare. A 72-year-old Caucasian male presented to the hospital with abdominal discomfort and acute renal insufficiency with a creatinine of 290 µmol/L. The clinical course, laboratory results and urinalysis were suspect for tubular injury. Renal biopsy showed calcium oxalate depositions. Elevated plasma and urine oxalate levels established the diagnosis oxalate nephropathy. The abdominal complaints with steatorrhea and positive anti-tissue transglutaminase antibodies were diagnosed as celiac disease, which was confirmed after duodenal biopsies. Treatment with prednisone, and gluten-free, low oxalate and normal calcium diet, lowered the plasma oxalate levels and improved his renal function. Decreased absorption of free fatty acids can lead to increased free oxalate in the colon due to the binding of free fatty acids to calcium, preventing the formation of the less absorbable calcium oxalate in the colon. Oxalate dispositions in the kidney can lead to acute tubular injury and chronic renal insufficiency. Celiac disease is therefore one of the intestinal diseases that can lead to hyperoxaluria and oxalate nephropathy.</p

Predictors of renal flares and long-term renal outcome in patients with lupus nephritis:results from daily clinical practice

OBJECTIVES: To describe renal outcomes of the lupus nephritis (LN) population of the University Medical Centre Groningen (UMCG) in the Netherlands and to identify predictors for renal flares and long-term renal outcome in daily clinical practice. METHODS: A retrospective analysis of biopsy-proven LN patients with induction and maintenance treatment in the UMCG between 1982 and 2016 was performed. Data were collected at time of diagnosis, after 6 months and every year up to 10 years after diagnosis. Outcome measures were renal relapse (biopsy proven), progression to chronic kidney disease (CKD) stage 3 or 4 and chronic renal replacement therapy. The ability of serum creatinine, proteinuria, creatinine clearance, serum anti-double stranded DNA (anti-dsDNA) antibodies, serum complement 3 (C3) and serum complement 4 (C4), as well as biographic data and histopathological class to predict long-term renal outcome was assessed. RESULTS: Seventy-one patients were included, with median follow-up of 120 months (IQR 48-120 months). During follow-up - up to 10 years - twenty-one (30%) patients experienced at least one relapse. Eleven (15%) patients had CKD stage 3 or 4, of whom eight showed persistent CKD since baseline and two (3%) patients required chronic renal replacement therapy. At baseline, low levels of serum C3 were a significant predictor of renal relapse. Low levels of C3 and C4 at 6 and 12 and proteinuria and high levels of anti-dsDNA at 12 months were significant predictors of renal relapse. At baseline, 6 months and 12 months serum creatinine and creatinine clearance were significant predictors for persistent or newly developed CKD 3 or 4, and need for chronic renal replacement therapy. CONCLUSIONS: Almost one-third of LN patients experience at least one renal relapse during long-term follow up, but only 3% need chronic renal replacement therapy. Our data suggests that early serological remission is associated with a low risk of renal relapse. Decreased renal function at onset and the first year after diagnosis is predictive for decreased renal function at a later stage

Staphylococcus aureus and Wegener's granulomatosis

Wegener's granulomatosis (WG) is a form of systemic vasculitis. It is characterized by granulomatous inflammation in the upper and lower airways, vasculitis and necrotizing glomerulonephritis, and is strongly associated with antineutrophil cytoplasmic antibodies against proteinase 3. Since the etiology of the disease is not clear, treatment, consisting of corticosteroids and immunosuppressives, is nonspecific and associated with severe side effects. Pinpointing the trigger(s) of the disease would highly improve treatment. Clinical evidence shows that an infectious agent, the bacterium Staphylococcus aureus, is a risk factor for disease relapse, suggesting its involvement in the pathogenesis of WG. Here we review both clinical and experimental data that either indicate or support a role for S. aureus in WG

Regulatory and effector B cell cytokine production in patients with relapsing granulomatosis with polyangiitis

Background: B cells are capable of producing regulatory and effector cytokines. In patients with granulomatosis with polyangiitis (GPA), skewing of the pro- and anti-inflammatory cytokine balance may affect the risk of relapse. This study aimed to investigate differences in B cell cytokine production in patients with relapsing GPA and in controls, and determine whether this can aid in relapse prediction. Methods: Thirteen GPA patients with an upcoming relapse were matched with non-relapsing patients and healthy controls in a retrospective design. The B cell subset distribution was determined from peripheral blood. Cryopreserved peripheral blood mononuclear cells were cultured and intracellular B cell production of regulatory (IL10) and effector (TNF alpha, IFN gamma IL2, IL6) cytokines was assessed. Finally, serum markers associated with B cell activation (sCD27) and migration (CCL19) were determined. Results: GPA patient samples exhibited significantly lower percentages of TNF alpha+B cells than controls, an effect that was most pronounced in patients about to relapse. B cell capacity for IL10 production was similar in patients and controls. No significant differences were observed for cytokine production in relapsing and non-relapsing GPA patients. TNFa production correlated strongly with IL2, IFN gamma and the percentage of memory B cells. No change in effector cytokines occurred before relapse, while the percentage of IL10+B cells significantly decreased. GPA patients in remission had increased serum levels of CCL19 and sCD27, and sCD27 levels increased upon active disease. Conclusions: While differences in effector B cell cytokine production were observed between patients and controls, monitoring this in GPA did not clearly distinguish patients about to relapse. Prospective measurements of the regulatory cytokine IL10 may have potential for relapse prediction. Memory B cells appear mainly responsible for effector cytokine production. Increased migration of these cells could explain the decreased presence of TNF alpha+B cells in the circulation

Conservation off the Port Bow

The Applied Biodiversity Sciences Perspectives Series is a student-directed collection of contributions from graduate student and faculty members of the integrative, NSF-IGERT Applied Biodiversity Sciences (ABS) program at Texas A&M University. The ABS Perspectives Series aims to highlight the application and practice of conservation science reflected in the experiences of ABS Scholars from both the social and biological sciences.Our online publication focuses on sharing our experiences with a diverse readership to raise awareness of biodiversity conservation issues and current research being undertaken at Texas A&M University. A foundational component of the ABS Program is to communicate within, across, and outside of our scientific disciplines. The ABS Perspectives Series is intended to communicate to the general public, the communities where our research takes place, fellow academics and practitioners, and institutions that provide logistics, infrastructure, and support the who, what, where, how, and why of Applied Biodiversity Science.Applied Biodiversity Science Program - Texas A&M Universit

Mycophenolic acid and 6-mercaptopurine both inhibit B-cell proliferation in granulomatosis with polyangiitis patients, whereas only mycophenolic acid inhibits B-cell IL-6 production

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates

Is serum HMGB1 a biomarker in ANCA-associated vasculitis?

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic inflammatory disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), Churg-Strauss syndrome and renal limited vasculitis (RLV). Extracellular high-mobility group box 1 (HMGB1) acts as an alarmin and has been shown to be a biomarker of disease activity as well as an autoantigen in systemic lupus erythematosus (SLE) and, possibly, in AAV. This study aims to assess antibodies against HMGB1 and HMGB1 levels as biomarkers for AAV disease activity and predictors of relapsing disease.Methods: AAV patients with active disease and healthy controls (HC) were evaluated for anti-HMGB1 antibodies while serum HMGB1 levels were measured longitudinally in AAV patients at presentation, during remission, prior to and at relapses.Results: HMGB1 levels were similar between AAV patients at presentation (n = 52) and HC (n = 35) (2.64 +/- 1.80 ng/ml vs. 2.39 +/- 1.09 ng/ml; P = 0.422) and no difference regarding HMGB1 levels could be found among AAV disease subsets (GPA: 2.66 +/- 1.83 ng/ml vs. MPA: 3.11 +/- 1.91 ng/ml vs. RLV: 1.92 +/- 1.48 ng/ml; P = 0.369). AAV patients with renal involvement had lower HMGB1 levels than patients without renal involvement at presentation (2.35 +/- 1.48 ng/ml vs. 3.52 +/- 2.41 ng/ml; P = 0.042). A negative correlation was observed between HMGB1 levels and 24-hour proteinuria (rho = -0.361, P = 0.028). Forty-nine AAV patients were evaluated for HMGB1 levels during follow-up and no differences were observed between relapsing and nonrelapsing patients (P = 0.350). No significant increase in HMGB1 levels was observed prior to a relapse compared with the remission period and changes in HMGB1 levels were not associated with an increased risk for relapse in AAV. Positivity for anti-HMGB1 antibodies was low in patients with active AAV (three out of 24 patients).Conclusions: Serum HMGB1 levels at presentation are not increased and are lower in patients with renal involvement. Relapses are not preceded or accompanied by significant rises in HMGB1 levels and changes in HMGB1 levels are not related to ensuing relapses. Anti-HMGB1 antibodies are present in only a few patients in AAV. in contrast to SLE, HMGB1 is not a useful biomarker in AAV.Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 GZ Groningen, NetherlandsUniversidade Federal de São Paulo, Escola Paulista Med Unifesp EPM, Div Rheumatol, BR-04023900 São Paulo, BrazilUniv Groningen, Univ Med Ctr Groningen, Dept Lab Med, NL-9713 GZ Groningen, NetherlandsUniv Groningen, Univ Med Ctr Groningen, Div Nephrol, Dept Internal Med, NL-9713 GZ Groningen, NetherlandsMartini Hosp, Dept Rheumatol & Internal Med, NL-9728 NT Groningen, NetherlandsUniversidade Federal de São Paulo, Escola Paulista Med Unifesp EPM, Div Rheumatol, BR-04023900 São Paulo, BrazilWeb of Scienc