INVITED REVIEW: Nutritional and management factors that influence colostrum production and composition in dairy cows.

Colostrum is a rich source of nutritional and non-nutritional components and is recognized as essential to transfer passive immunity to newborn calves. Because of the individual and seasonal variability in colostrum yield and composition, maintaining an adequate supply of high-quality colostrum year-round remains a challenge for commercial dairy producers. In this narrative review, we described the individual, seasonal, and herd-level variability of colostrum production and summarized the association between individual animal factors such as parity, sex of the calf, calf birth weight, as well as indicators of the cow's metabolic status and the yield and composition of colostrum. Further, we reviewed the current knowledge on the influence of prepartum nutrition and management strategies on colostrum production. Research on the metabolizable energy and protein supplied in the prepartum diet as well as into the inclusion and source of vitamins, minerals, and feed additives suggests prepartum nutrition influences the yield, quality, and composition of colostrum. Furthermore, the prepartum environment and dry period length remain influential factors in the production of colostrum. However, additional research is needed to understand the mechanisms by which prepartum nutrition and management affects colostrum production. Lastly, time to colostrum harvest and oxytocin administration as well as the current knowledge on the effect of heat-treatment and colostrum storage strategies on colostral components were discussed. To conclude, we identify critical gaps in knowledge for future focus of investigation in colostrum research.

Effect of replacing a portion of inorganic chloride trace minerals with trace mineral amino acid complexes.

The objective was to determine whether replacing a portion of inorganic chloride trace minerals and cobalt carbonate in the diet with AA complexes of trace minerals and cobalt glucoheptonate will improve lactating cow performance, feed efficiency, and calf performance. In a clinical trial, 69 Holstein cows entering second lactation and greater were randomly assigned to 1 of 2 treatments, with the total dietary trace mineral concentration the same between treatments, starting 1 wk after dry off (50 to 57 d before expected parturition) until 154 d in milk (DIM): (1) an inorganic chloride trace mineral (ITM) blend consisting of Zn (75 mg/kg), Mn (65 mg/kg), and Cu (10 mg/kg) as hydroxychlorides and Co (1 mg/kg) as carbonate (n = 37) or (2) partial replacement of ITM with AA complexes of Zn (40 mg/kg), Mn (20 mg/kg), and Cu (3.5 mg/kg) and Co glucoheptonate (1 mg/kg; AATM; Availa-Dairy, Zinpro Corp.; n = 32). Dry matter intake (DMI) was recorded daily from enrollment through wk 8, and milk yields were recorded daily from calving through wk 22. Milk composition and body weights (BW) were collected weekly. Serum samples were analyzed for albumin (Alb), cholesterol (Chol), total bilirubin (Bili), aspartate aminotransferase (AST), haptoglobin, ß-hydroxybutyrate (BHB), and Ca. A liver health index (LHI) was calculated based on Bili, Chol, and Alb concentrations. A liver functionality index (LFI) was calculated to standardize changes in Alb, Chol, and Bili from 4 to 29 DIM. Greater LHI and LFI indicate better health status. Colostrum was analyzed for IgG and Brix, and calf serum was analyzed for IgG. Calf growth was monitored through 9 wk of age (AATM: n = 12, ITM: n = 10). Data were analyzed using SAS software with mixed effects models and repeated-measures analysis, when applicable. Survival analysis for pregnancy by 154 DIM was analyzed by Cox proportional and Kaplan-Meier hazards models. Disorder incidence was tested with Fisher's exact test. Prepartum DMI as a percent of BW was lower in cows fed AATM and not significant postpartum. Cows fed AATM produced more milk from wk 1 to 8 and from wk 1 to 22. Energy-corrected milk yield and colostrum measures did not significantly differ between treatments. A treatment by time interaction was seen for AST and BHB; cows fed AATM tended to have lower AST concentrations at 28 DIM and lower concentrations in BHB through 29 DIM, though not statistically significant. Cows fed AATM had greater LHI at 4 DIM. Haptoglobin, Ca, LFI, hazard of pregnancy, risk to first service, survival curves, or services per pregnancy did not significantly differ. Calf serum IgG and birth weight did not significantly differ between treatments. Calves from dams fed AATM had greater average daily gain than calves from dams fed ITM. Overall, cows fed AATM during the dry period and early lactation had improved postpartum performance and potential health improvements.

High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

Epidemiology of bovine colostrum production in New York Holstein herds: Prepartum nutrition and metabolic indicators.

Colostrum yield and quality are influenced by prepartum nutrition and the metabolic status of the cow; however, data considering these associations on multiple dairy farms are limited. Our objective was to identify cow-level prepartum metabolic indicators, as well as farm-level nutritional strategies associated with colostrum yield and the indicator of colostrum quality, Brix %. A convenience sample of 19 New York Holstein dairies (median: 1,325 cows; range: 620 to 4,600 cows) were enrolled in this observational study. Records for individual colostrum yield and Brix % were collected by farm personnel between October 2019 and February 2021. Farms were visited 4 times, approximately 3 mo apart, to obtain feed samples of the prepartum diets, collect blood samples from 24 pre- and postpartum cows, respectively, and determine prepartum body condition score. Feed samples were submitted for analysis of chemical composition, and particle size was determined on-farm using a particle separator. Prepartum serum samples (n = 762) were analyzed for glucose and nonesterified fatty acid concentrations. Whole blood from postpartum cows was analyzed for herd prevalence of hyperketonemia (proportion of samples with ß-hydroxybutyrate ≥1.2 mmol/L). A cohort of primiparous (PP; n = 1,337) and multiparous (MPS; n = 3,059) cows calving ± 14 d of each farm visit were included in the statistical analysis. Animals calving in this period were assigned results for the close-up diet composition and herd prevalence of hyperketonemia collected from the respective farm visit. Greatest colostrum yield from PP and MPS cows was associated with moderate starch [18.6-22.5% of dry matter (DM)] and a moderate herd prevalence of hyperketonemia (10.1-15.0%). Greatest colostrum yield from MPS cows was associated with moderate crude protein (13.6-15.5% of DM) and a less severe negative dietary cation-anion difference (DCAD; >-8 mEq/100 g), whereas greatest colostrum yield from PP cows was associated with low crude protein (≤13.5% of DM). In addition, a moderate proportion of the diet with particle length ≥19 mm (15.3-19.1%) was associated with lowest colostrum yield from PP and MPS cows. Highest colostrum Brix % was associated with prepartum dietary factors of low neutral detergent fiber (≤39.0% of DM) and high proportion of the diet with particle length ≥19 mm (>19.1%). In addition, low starch (≤18.5% of DM) and low and moderate DCAD level (≥-15.9 mEq/100 g) were associated with greatest Brix % from PP cows, whereas moderate DCAD (-15.9 to -8.0 mEq/100 g) was associated with greatest Brix % from MPS cows. Prepartum serum nonesterified fatty acid concentration ≥290 µEq/L was associated with increased colostrum yield, but prepartum serum glucose concentration and body condition score were not associated with colostrum yield or Brix %. These data provide nutritional and metabolic variables to consider when troubleshooting colostrum production on farms.

[Frequency and severity of sarcopenia in patients with inflammatory and noninflammatory musculoskeletal diseases : Results of a monocentric study in a tertiary care center]. / Häufigkeit und Schweregrad von Sarkopenie bei Patient*innen mit entzündlichen und nichtentzündlichen muskuloskeletalen Erkrankungen : Ergebnisse einer monozentrischen Studie in einem tertiären Zentrum.

INTRODUCTION: Sarcopenia (SP) is defined as the pathological loss of muscle mass and function. This is a clinically relevant problem, especially in geriatric patients, because SP is associated with falls, frailty, loss of function, and increased mortality. People with inflammatory and degenerative rheumatic musculoskeletal disorders (RMD) are also at risk for developing SP; however, there is little research on the prevalence of this health disorder in this patient group using currently available SP criteria. OBJECTIVE: To investigate the prevalence and severity of SP in patients with RMD. METHODS: A total of 141 consecutive patients over 65 years of age with rheumatoid arthritis (RA), spondylarthritis (SpA), vasculitis, and noninflammatory musculoskeletal diseases were recruited in a cross-sectional study at a tertiary care center. The European Working Group on Sarcopenia in Older People (EWGSOP 1 and 2) definitions of presarcopenia, SP, and severe SP were used to determine the prevalence. Lean mass as a parameter of muscle mass and bone density were measured by dual X­ray absorptiometry (DXA). Handgrip strength and the short physical performance battery (SPPB) were performed in a standardized manner. Furthermore, the frequency of falls and the presence of frailty were determined. Student's T-test and the χ2-test were used for statistics. RESULTS: Of the patients included 73% were female, the mean age was 73 years and 80% had an inflammatory RMD. According to EWGSOP 2, 58.9% of participants probable had SP due to low muscle function. When muscle mass was added for confirmation, the prevalence of SP was 10.6%, 5.6% of whom had severe SP. The prevalence was numerically but not statistically different between inflammatory (11.5%) and noninflammatory RMD (7.1%). The prevalence of SP was highest in patients with RA (9.5%) and vasculitis (24%), and lowest in SpA (4%). Both osteoporosis (40% vs. 18.5%) and falls (15% vs. 8.6%) occurred more frequently in patients with SP than those without SP. DISCUSSION: This study showed a relatively high prevalence of SP, especially in patients with RA and vasculitis. In patients at risk, measures to detect SP should routinely be performed in a standardized manner in the clinical practice. The high frequency of muscle function deficits in this study population supports the importance of measuring muscle mass in addition to bone density with DXA to confirm SP.

Eucalcemia during lipopolysaccharide challenge in postpartum dairy cows: I. Clinical, inflammatory, and metabolic response.

Hypocalcemia induced by immune activation is a conserved response across mammalian species; however, administration of Ca is discouraged in other species as it is associated with increased morbidity and mortality. Early postpartum cows experience a decrease in circulating Ca concentration following acute inflammation. Corrective Ca therapy during the transition period, particularly in dairy cows experiencing acute disease, is common practice. However, the effect of Ca administration on the inflammatory response during acute immune activation is unknown. Our objective was to compare the clinical, inflammatory, and metabolic response to an intravenous (IV) lipopolysaccharide (LPS) challenge between postpartum cows infused, or not, with IV Ca to maintain eucalcemia. Cows (n = 14, 8 ± 1 d in milk) were enrolled in a matched-pair randomized controlled design to receive IV Ca (IVCa) or sterile 0.9% NaCl (CTRL) during an IV LPS challenge (0.040 or 0.045 µg of LPS/kg of body weight over 1 h). Ionized Ca (iCa) was monitored cow-side, and IV Ca infusion was adjusted in a eucalcemic clamp for 12 h following the start of LPS infusion. Cows were monitored during the 24 h following challenge and serial blood samples were collected to quantify concentrations of glucose, ß-hydroxybutyrate, nonesterified fatty acids, urea nitrogen, cytokines, acute-phase proteins, and cortisol. Blood iCa concentration decreased to 0.87 ± 0.03 mM in CTRL during challenge, and by design, iCa concentration was maintained within 3% of baseline in IVCa. Body temperature, heart rate, and respiratory rate were monitored for 24 h following the start of challenge and did not differ between groups. A treatment × time interaction was identified such that serum cortisol concentrations increased in both groups at 2 h but decreased to a greater extent at 6 h in IVCa compared with CTRL. Rumination time (min/h) over the first 12 h following challenge was greater in IVCa, but total rumination time in the 24 h following challenge did not differ from CTRL. Serum glucose and nonesterified fatty acid concentrations decreased, and ß-hydroxybutyrate and urea nitrogen concentrations increased over time, but did not differ between groups. Acute leukopenia occurred in both groups at 4 h before leukocytosis was observed at 24 h with total white blood cell counts returning to baseline within 72 h. Plasma concentrations of tumor necrosis factor (TNF) and interleukin-10 (IL-10) increased within 1 h following the start of challenge and did not differ between groups. Serum haptoglobin and serum amyloid A concentrations increased within the 24 h following challenge and were elevated through 72 h but did not differ between groups. Eucalcemia during the acute systemic inflammatory response did not alter the TNF or IL-10 cytokine response, or the acute-phase protein SAA and haptoglobin response in this LPS challenge model; however, eucalcemia was associated with a more rapid decline in cortisol response and greater rumination time in the first 12 h following challenge. We did not find evidence that eucalcemia exacerbated the inflammatory response in early postpartum cows, but Ca administration may alter the clinical response to acute systemic inflammation.

Eucalcemia during lipopolysaccharide challenge in postpartum dairy cows: II. Calcium dynamics.

Hypocalcemia induced by immune activation is a conserved response among mammals. Early postpartum cows will experience decreased circulating Ca concentrations following acute immune activation; however, the cause for decreased Ca concentration is unknown. Our objectives were to (1) describe Ca dynamics following an intravenous (IV) LPS challenge in early postpartum cows, and (2) compare inflammatory-induced changes in Ca dynamics between IV Ca-treated cows and control cows. Cows (n = 14, 8 ± 1 d in milk) were enrolled in a matched-pair randomized controlled design to receive IV Ca (IVCa) in a eucalcemic clamp for 12 h, or 0.9% NaCl (CTRL) following an IV LPS infusion (0.040 or 0.045 µg of LPS/kg of body weight over 1 h). During the 24 h following LPS infusion, circulating concentrations of parathyroid hormone and serotonin were measured, serum and urine samples were collected to calculate urinary fractional excretion of Ca (FECa), and fecal samples were collected to calculate Ca apparent digestibility (ADCa) using amylase-treated and ash-corrected undigested neutral detergent fiber after 240 h (uNDFom240) as an internal marker. Changes in Ca intake and milk Ca secretion were also quantified and compared with baseline values. Cows were fasted during challenge and dry matter intake was 20 ± 5% less than baseline values on the day of challenge and did not differ between groups. On the day of challenge, milk Ca concentration increased, but milk yield decreased such that total Ca secreted in milk did not change from baseline. Urine FECa was low overall, but an interaction of treatment and time was identified such that FECa increased in IVCa but decreased in CTRL. Concentrations of parathyroid hormone increased and serotonin decreased following challenge. Fecal dry matter decreased from baseline, but did not differ between 6, 12, and 24 h, and did not differ between groups. An interaction of treatment and time was identified for ADCa and apparent digestibility of dry matter such that digestibility was decreased in CTRL but not IVCa at 6 h. Acute immune activation induced hypocalcemia in CTRL, and although urinary Ca excretion was not a primary cause, it is unclear to what degree hypocalcemia was due to altered ADCa. Eucalcemia appeared to alter adaptations in Ca homeostasis during immune activation as FECa was increased in IVCa animals.

Epidemiology of bovine colostrum production in New York Holstein herds: Cow, management, and environmental factors.

Adequate supply of high-quality colostrum is essential for calf health. Colostrum production, at first milking, varies between animals and seasons, but herd-level and management associations with colostrum production have not been well described. Our objectives were to (1) describe colostrum production and colostrum handling practices and (2) to identify individual cow, herd management, and environmental factors associated with colostrum production. A convenience sample of 19 New York Holstein dairy farms (620 to 4,600 cows) were enrolled in this observational study to describe colostrum production and to evaluate cow, management, and prepartum environmental factors associated with colostrum yield and Brix %. Herd owners or managers were given a colostrum management questionnaire, and farm personnel recorded individual colostrum yield and Brix % for primiparous (PP; n = 5,978) and multiparous (MPS; n = 13,228) cows between October 2019 and February 2021. Temperature, relative humidity, and light intensity were measured by sensors placed in each farm's close-up dry cow pens for the entire length of the study. Median colostrum yield for each farm ranged from 2.5 to 7.6 kg for PP and 4.0 to 7.7 kg for MPS cows. Mean Brix % from each farm ranged from 22.2 to 27.9% for PP and 22.0 to 28.8% for MPS cows. Lowest colostrum yield from PP animals was associated with calf sex (female) and colostrum Brix % (≤22%). Greatest colostrum yield from MPS cows was associated with colostrum Brix % (≤22%), calf sex (twin), dry period length (>67 d), gestation length (283-293 d), an alive calf, second parity, previous lactation length (>344 d) and previous lactation 305-d mature equivalent milk yield (>13,091 kg), heat and humidity exposure area under the curve (AUC) 7 d before calving (>69.2 average temperature-humidity index per 30-min interval), and light intensity AUC 14 d before calving (>154.2 average lux per 15-min interval). Greatest colostrum Brix % from PP animals was associated with calf sex (male), an alive calf, and light intensity AUC 14 d before calving (≤64.0 average lux per 15-min interval). Greatest colostrum Brix % from MPS cows was associated with dry period length (>67 d), an alive calf, 305-d mature equivalent milk yield of previous lactation (≤15,862 kg), gestation length (274-282 d), colostrum yield (<6 kg), fifth or greater parity, and heat and humidity exposure AUC 7 d before calving (≤50.1 average temperature-humidity index per 30-min interval). Dairy producers can use this information to recognize the variation in colostrum production and alter colostrum management programs in anticipation of periods of low production or quality.

Lipopolysaccharide challenge following intravenous amino acid infusion in postpartum dairy cows: I. Production, metabolic, and hormonal responses.

Postpartum cows experience a nadir in energy and AA deficit early postpartum. At the same time, cows are challenged with inflammatory stimuli and often show heightened immune responsiveness, further increasing their metabolic needs during this critical time. This study investigated the response to a systemic inflammatory stimulus after a 4-d intravenous (IV) AA infusion designed to ameliorate the estimated metabolizable protein (MP) deficit in postpartum cows. Our objectives were to (1) describe the production and metabolic responses to early postpartum IV AA infusion, (2) determine the metabolic and hormonal responses to an acute IV lipopolysaccharide (LPS) challenge in early postpartum cows, and (3) compare these metabolic and hormonal responses between IV AA treated and control cows. Cows (n = 14, 4 ± 1 d in milk) were continuously IV infused for 4 d in a matched-pair randomized controlled design and received IV AA (IVAA) or 0.9% NaCl (CTRL). Treatment with IV AA consisted of 1 g/kg of BW per day of combined essential AA (EAA) and nonessential AA (NEAA). After infusion ended, cows were challenged IV with LPS (0.0625 µg/kg of BW over 1 h), and serial blood samples were collected to quantify AA, metabolite, and hormone concentrations. Amino acid infusion increased plasma EAA and NEAA concentrations and ameliorated the estimated MP deficit but not the metabolizable energy deficit in IVAA cows. Patterns of dry matter intake during infusion were different between groups. Milk yield and milk protein content and yield were unaffected, but IV AA was associated with increased milk fat content and yield of both de novo and preformed fatty acids. Before LPS infusion, plasma EAA and NEAA concentrations were greater in IVAA compared with CTRL. During LPS challenge, plasma AA concentrations decreased to a greater degree in IVAA than CTRL. Glucagon concentrations were greater and glucose concentrations lower in IVAA during challenge; however, previous AA infusion did not affect the time-dependent changes in concentrations of energy metabolites or glucoregulatory hormones. Plasma urea nitrogen concentration increased in both treatments following challenge, although the temporal pattern depended on treatment. Effects of AA infusion on milk fat response were pronounced and likely due to a combination of increased lipolysis and de novo milk fat synthesis. Despite differences in circulating concentrations of nutrients and hormones before challenge, metabolic responses to systemic inflammation did not differ between the 2 treatments. We conclude that AA infusion changed metabolic status and milk fat but did not appear to alter the metabolic response to subsequent systemic inflammation.

Lipopolysaccharide challenge following intravenous amino acid infusion in postpartum dairy cows: II. Clinical and inflammatory responses.

Amino acids (AA) are integral nutrients for a functioning immune system. Postpartum cows experience AA deficits early postpartum that may influence the response to immune activation. This study investigated the clinical and inflammatory responses to a systemic inflammatory stimulus after a 4-d intravenous (IV) AA infusion with a mix of essential and nonessential AA designed to ameliorate the estimated metabolizable protein deficit in early postpartum cows. Our objectives were (1) to describe the clinical and inflammatory response to an acute IV lipopolysaccharide (LPS) challenge in early postpartum cows, and (2) to compare these clinical and inflammatory responses between IV AA-treated and control cows. Cows (n = 14, 4 ± 1 d in milk) were continuously infused IV for 4 d in a matched-pair randomized controlled design and received 0.9% NaCl (CTRL) or IV AA (IVAA) to supply 1 g/kg of BW per day of combined essential and nonessential AA. After infusion ended, cows were challenged with IV LPS (0.0625 µg/kg of BW over 1 h), and serial blood samples were collected for complete blood cell counts and to quantify plasma cytokines and acute-phase proteins. Body temperature, heart rate, and respiratory rate were monitored for 24 h during challenge. During challenge, maximum body temperature was greater in IVAA (41.3 ± 0.20°C) than in CTRL (40.6 ± 0.19°C). In both groups, respiratory rate increased during the first 2 h following challenge, whereas heart rate first decreased over the first 2 h and then increased to reach a maximum at 4 h. Acute leucopenia occurred within 1 h of challenge in both groups before leukocytosis was observed at 24 h, with white blood cell counts returning to baseline values within 72 h. Plasma haptoglobin and serum amyloid A concentrations increased 3-fold and 4-fold in both groups and peaked at 48 and 24 h following challenge, respectively. Plasma concentrations of TNF-α and IL-10 increased within 1 h and peaked at 2 h following the start of challenge. Plasma IL-10 concentrations increased to a greater extent in CTRL compared with IVAA during challenge. Despite differences in IL-10 concentration, previous AA infusion did not alter the acute-phase protein response to LPS challenge. We conclude that AA infusion before systemic inflammatory challenge decreased the anti-inflammatory response but did not alter concentrations of other systemic markers of inflammation.

[Are SARS-CoV-2 reactive T cells detectable and potentially protective in patients under anti-CD20 treatment with an impaired humoral response?] / Sind SARS-CoV-2-reaktive T­Zellen bei Patienten unter Anti-CD20-Therapie mit einer beeinträchtigten humoralen Antwort nachweisbar und potenziell protektiv?

The pandemic attributable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has greatly changed life in most countries of the world for more than 1.5 years now. The spread could be more or less well-controlled and fatalities could partly be avoided by obligatory wearing of masks, contact restrictions and since the beginning of the year by vaccinations. Patients with chronic inflammatory diseases and organ transplant patients under immunosuppression, are somewhat more at risk to become ill with coronavirus disease 2019 (COVID-19). The probability and severity of an infection depends on the ability of the humoral and cellular immune systems to effectively combat the virus. This can be substantially improved by vaccination. The B cell depleting monoclonal antibody rituximab (RTX) is frequently employed in rheumatic diseases, whereby antibody formation against the new pathogen within the framework of vaccination is restricted. Recent study results in patients treated with RTX indicate that an effective cellular immune response can be developed despite the impaired humoral response.

Biomarkers in acute kidney injury - pathophysiological basis and clinical performance.

Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies.

Treat-to-target (T2T) recommendations for gout.

OBJECTIVES: The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. METHODS: A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. RESULTS: Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. CONCLUSIONS: This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.

Prediction of cardiovascular events after renal transplantation.

BACKGROUND: Pulse wave velocity (PWV) is a marker of arterial stiffness and predicts cardiovascular events in the nontransplantation population. Cardiovascular events (CVE) are the leading cause of death and one of the leading causes of graft failure in renal transplant recipients. The present prospective study investigates whether there is a correlation between PWV and CVE in renal transplant recipients. METHODS: A prospective study assessing the incidence of a composite cardiovascular endpoint within ≥ 3 years after pulse wave analysis was performed in 64 stable renal transplant recipients. Measurement of PWV, augmentation index (AI75), and aortic systolic pressure was conducted using the SphygmoCor (AtCor) device. The composite endpoint of the study was the incidence of either death, myocardial infarction, stroke, or admission for symptomatic intermittent claudication or decompensated congestive heart failure. RESULTS: Fifteen patients (23%) reached the composite endpoint during a follow-up of 4.4 years. Binary logistic regression using PWV, AI75, central aortic systolic pressure, peripheral systolic pressure, and pulse pressure as covariates revealed that PWV was significantly associated with cardiovascular events (10.1 ± 3.6 m/s in subjects reaching the endpoint vs 8.5 ± 1.5 m/s in subjects not reaching the endpoint; P = .048). CONCLUSION: Increased arterial stiffness as assessed by PWV predicts CVE in renal transplant recipients and may be regarded as a footprint of accelerated arteriosclerosis for those patients.

Clindamycin-primaquine for pneumocystis jiroveci pneumonia in renal transplant patients.

BACKGROUND: Trimethoprim/sulfamethoxazole (TMP/SMX) is considered first-line therapy for pneumocystis jiroveci pneumonia (PCP) in renal transplant patients. Alternatives have not been formally studied. Clindamycin-primaquine (C-P) is effective in HIV-associated PCP, but data in renal transplant patients are lacking. PATIENTS AND METHODS: Retrospective cohort study of 57 consecutive renal transplant patients who developed PCP and were treated with C-P (n = 23) or TMP/SMX (n = 34). RESULTS: A non-significantly higher failure rate was observed in patients on C-P due to lack of efficacy (30.4 versus 20.6%, p = 0.545). The difference was more pronounced in severe PCP (60 versus 37.5%, p = 0.611) and a significantly lower efficacy of C-P was seen when used as salvage therapy. The two patients who had received C-P after not responding to TMP/SMX failed this regimen, but all seven patients who had failed initial treatment with C-P and had been switched to TMP/SMX were cured (p = 0.028). No treatment-limiting adverse reactions were reported for patients on C-P while six patients (17.6%) on TMP/SMX developed possibly related treatment-limiting toxicity (p = 0.071). However, in only two patients adverse events were definitely related to TMP/SMX (5.9%). CONCLUSIONS: Clindamycin-primaquine appears to be safe and well tolerated for treating PCP in renal transplant patients but is probably less effective than TMP/SMX, the standard regimen. However, our data indicates that C-P represents an acceptable alternative for patients with contraindications or treatment emergent toxicities during TMP/SMX use. Notably, TMP/SMX was also acceptably tolerated in most patients. TMP/SMX remains an effective salvage regimen in case of C-P failure.

The impact of aerobic exercise on blood pressure variability.

There is increasing evidence that blood pressure variability (BPV, variation of blood pressure over time) constitutes a strong and independent marker of cardiovascular risk. The all-cause mortality is >50% greater in subjects with a standard deviation of inter-visit blood pressure >5 mm Hg. Regular aerobic exercise reduces blood pressure and is recommended by current hypertension guidelines as a basic lifestyle modification. It remains elusive, however, whether aerobic exercise is able to reduce BPV as well. In total, 72 hypertensive subjects were randomly assigned to an 8-12-week treadmill exercise program (target lactate 2.0±0.5 mmol l(-1)) or sedentary control. Blood pressure was measured by 24 h-ambulatory blood pressure monitoring (ABP). Two aspects of BPV were assessed: the variability of ABP and the variability of blood pressure on exertion. The coefficient of variation (CV) was used as a statistical measure of BPV. The CV of systolic daytime ABP was defined as primary outcome. The exercise program significantly decreased systolic and diastolic daytime ABP by 6.2±10.2 mm Hg (P<0.01) and 3.0±6.3 mm Hg (P=0.04), respectively. Moreover, it reduced blood pressure on exertion and increased physical performance (P<0.05 each). Exercise had no impact, however, on the CV of daytime (10.2±2.7 vs. 9.8±2.6%, P=0.30) and night-time systolic (8.9±3.2 vs. 10.5±4.1%, P=0.10) and diastolic ABP (daytime 11.5±3.3 vs. 11.5±3.1%, night-time 12.0±4.3 vs. 13.8±5.2%; P>0.05 each). Regular aerobic exercise is a helpful adjunct to control blood pressure in hypertension, but it has no effect on 24 h- BPV, an independent predictor of cardiovascular risk.

Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury.

BACKGROUND: Urinary calprotectin has recently been identified as a promising biomarker for the differentiation of pre-renal and intrinsic acute kidney injury (AKI). This study compares the diagnostic performance of calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) in this differential diagnosis. METHODS: Urinary calprotectin and NGAL concentrations were assessed in a study population of 87 subjects including 38 cases of intrinsic AKI, 24 cases of pre-renal AKI and 25 healthy controls. Urinary tract obstruction, renal transplantation and metastatic cancer were defined as exclusion criteria. RESULTS: Mean calprotectin concentrations were significantly lower in pre-renal (190.2 ± 205.7 ng mL(-1) ) than in intrinsic AKI (6250.1 ± 7167.2 ng mL(-1) , P < 0.001). Receiver-operating characteristic (ROC) analysis provided an AUC of 0.99. Mean NGAL concentrations were significantly higher in intrinsic than in pre-renal AKI as well (458.1 ± 695.3 vs. 64.8 ± 62.1 ng mL(-1) , P = 0.001) providing an AUC of 0.82. A combination of the present study population with the cohort of the proof of concept study led to a population of 188 subjects (58 pre-renal AKI, 90 intrinsic AKI, 40 healthy controls). ROC analyses provided an AUC of 0.97 for calprotectin and 0.76 for NGAL yielding sensitivity and specificity values of 93.3 and 94.8% (calprotectin) vs. 75.3 and 72.4% (NGAL). Optimal cut-off values were 440 ng mL(-1) (calprotectin) and 52 ng mL(-1) (NGAL). Pyuria increased calprotectin concentrations independent of renal failure. CONCLUSION: This study shows that both calprotectin and NGAL are able to differentiate between pre-renal and intrinsic AKI after exclusion of pyuria. In the present population, calprotectin presents a higher sensitivity and specificity than NGAL.

Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine.

BACKGROUND: Recurrent urinary tract infections (UTIs) increase mortality and reduce graft survival after renal transplantation. Strategies to prevent recurrent UTIs include L-methionine, cranberry juice, and antibiotics. Data on the efficacy of cranberry and L-methionine, however, are controversial in the general population; there are few data in renal transplant recipients. METHODS: We performed a retrospective analysis of 82 transplant recipients with recurrent UTIs, who underwent prophylaxis with cranberry juice (2 × 50 mL/d, n = 39, 47.6%), or L-methionine (3 × 500 mg/d, n = 25, 30.5%), or both modalities (n = 18, 21.9%). Thirty patients without prophylaxis served as controls. We analyzed symptoms, pyuria/nitrituria, and incidence of UTI events during 1 year before versus after initiation of prophylaxis. RESULTS: Prophylaxis highly significantly decreased the annual UTI incidence by 58.3% (P < .001) in the study population with no change in the control group (P = .85); in addition, 53.7% of symptomatic patients reported relief of symptoms and pyuria/nitrituria disappeared in 42.4% of the dipstick-positive patients (P < .001 each). Cranberry reduced the annual number of UTI episodes by 63.9% from 3.6 ± 1.4 to 1.3 ± 1.3/year (P < .001) and L-methionine by 48.7% from 3.9 ± 1.8 to 2.0 ± 1.3/year (P < .001). CONCLUSION: Cranberry juice and L-methionine successfully reduced the incidence of UTI after renal transplantation.