Association of Recipient APOL1 Kidney Risk Alleles With Kidney Transplant Outcomes.

BACKGROUND: Kidney transplant survival in African American recipients is lower compared with non-African American transplant recipients. APOL1 risk alleles (RA) have been postulated as likely contributors. We examined the graft outcomes in kidney transplant recipients (KTRs) stratified by APOL1 RA status in a multicenter observational prospective study. METHODS: The Renal Transplant Outcome Study recruited a cohort of incident KTRs at 3 transplant centers in the Philadelphia area from 1999-2004. KTRs were genotyped for APOL1 RA. Allograft and patient survival rates were compared by the presence and number of APOL1 RA. RESULTS: Among 221 participants, approximately 43% carried 2 APOL1 RA. Recipients carrying 2 APOL1 RA demonstrated lower graft survival compared with recipients with only 1 or none of APOL1 RA at 1 y posttransplant, independently of other donor and recipient characteristics (adjusted hazard ratio 3.2 [95% confidence interval, 1.0-10.4], P = 0.05). There was no significant difference in overall survival or graft survival after 3 y posttransplantation. There was no difference in death by APOL1 -risk status ( P = 0.11). CONCLUSIONS: Recipients with 2 APOL1 high-risk alleles exhibited lower graft survival 1 y posttransplantation compared with recipients with only 1 or 0 APOL1 RA. Further research is required to study the combined role of the recipient and donor APOL1 genotypes in kidney transplantation.

Baseline risk markers and visit-to-visit variability in relation to kidney outcomes - A post-hoc analysis of the PERL study.

BACKGROUND: Baseline risk variables and visit-to-visit variability (VV) of systolic blood pressure (SBP), HbA1c, serum creatinine, and uric acid (UA) are potential risk markers of kidney function decline in type 1 diabetes. METHODS: Post-hoc analysis of a double-blind randomized placebo-controlled clinical trial investigating allopurinol's effect on iohexol-derived glomerular filtration rate (iGFR) in type 1 diabetes with elevated UA. Primary outcome was iGFR change over three years. Linear regression with backwards selection of baseline clinical variables was performed to identify an optimized model forecasting iGFR change. Furthermore, VVs of SBP, HbA1c, serum creatinine, and UA were calculated using measurements from the run-in period; thereafter assessed by linear regression, with iGFR change as the dependent variable. RESULTS: 404 participants were included in the primary analyses. In the optimized baseline variable model, higher HbA1c, SBP, iGFR, albuminuria, and heart rate, and mineralocorticoid receptor antagonist prescription were associated with greater iGFR decline. Higher VV of SBP was associated with greater iGFR decline (adjusted ß (ml/min/1.73 m2/50 % increase): -0.79, p = 0.01). CONCLUSIONS: We identified several risk markers for faster iGFR decline in a high-risk population with type 1 diabetes. While further research is needed, our results indicate possible new and clinically feasible measures to risk stratify for DKD in type 1 diabetes.

Adipokines and coronary artery calcification in incident dialysis participants.

PURPOSE: Adipokines have been associated with increased risk of cardiovascular disease. Our aim was to determine if adipokine levels are associated with coronary artery calcification (CAC) as well as all-cause mortality in incident dialysis patients. METHODS: In patients new to dialysis, we prospectively investigated the association of adiponectin, leptin and resistin with coronary artery calcification measured by ECG-gated computer tomography. Participants were recruited a median of two months after starting dialysis. RESULTS: The mean age was 50.0 (12.6) years and 31.1% were women. About 42% percent had BMI > 30. Higher adiponectin levels were inversely associated with CAC progression as change in Agatston score [-155.1 (-267.9, -42.2), p = 0.008] or change in CAC volumes between scans [-2.8 (-4.9, -0.6), p = 0.01]. Higher leptin levels were associated with CAC progression [110.4 (34.3-186.6), p = 0.005]. Decreased leptin [HR 0.5 (0.3-0.9), p = 0.05] was associated with all-cause mortality in adjusted models. There was no significant association between all-cause mortality and adiponectin [1.4 (0.6-3.4), p = 0.4] or resistin [HR 1.7 (0.5-5.0), p = 0.4]. CONCLUSION: High adiponectin protects against CAC progression, but is not associated with increased all-cause mortality. Higher leptin, as well as higher leptin to adiponectin ratio, is associated with CAC progression. Lower leptin levels were associated with all-cause mortality. The association of adipokines and cardiovascular disease in individuals on dialysis is complex and requires further study.

IL-6 Is Associated with Progression of Coronary Artery Calcification and Mortality in Incident Dialysis Patients.

INTRODUCTION: Inflammation is important in the pathogenesis of atherosclerosis. Elevated interleukin-6 (IL-6) is associated with cardiovascular events and also predicts mortality in individuals with CKD. Our goal was to determine the association between IL-6, FGF23, and high-sensitivity C-reactive protein (hsCRP) on coronary artery calcification (CAC) progression and mortality in incident dialysis patients without prior coronary events. METHODS: A prospective cohort of incident adult dialysis participants had CAC measured by ECG-triggered multislice CT scans at baseline and at least 12 months later. Lipids, mineral metabolism markers, FGF23, and inflammatory markers, such as IL-6 and hsCRP, were measured at the baseline visit. RESULTS: Participants in the high IL-6 tertile had the highest baseline CAC score (133.25 [10.35-466.15]) compared to the low (0.25 [0-212.2]) and intermediate (29.55 [0-182.85]) tertiles. Almost half of the participants with high IL-6 (15 of 32 [46.9%]) experienced progression of CAC compared to participants with low (8 of 32 [25%]) and intermediate (9 of 32 [28.1%]) (p = 0.05) IL-6 levels. Each log increase in IL-6 was associated with increase in death (hazard ratio 2.2, 95% CI: 1.2-3.8; p = 0.01). After adjusting for smoking, age, gender, race, diabetes, phosphate, and baseline calcium score, IL-6 (log) was associated with 2.2 times (95% CI: 1.1-4.6; p = 0.03) increase in death. CONCLUSION: IL-6 is associated with progression of CAC and mortality in incident dialysis patients.

Treatment of Multiple Myeloma With Daratumumab in a Kidney Transplant Patient.

CLINICAL FEATURES: A middle-aged man with history of kidney transplantation was diagnosed with multiple myeloma (MM); he was treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for induction therapy. However, a repeat bone marrow biopsy after treatment revealed 10% clonal plasma cell involvement. Given residual disease, his treatment regimen was changed to daratumumab, bortezomib, and dexamethasone in an attempt to achieve minimal residual disease. THERAPEUTIC CHALLENGE: Daratumumab was recently approved for treatment of relapsed or refractory MM; there are no data regarding the safety and effectiveness in solid organ transplant patients. SOLUTION: Our patient was treated with a daratumumab-based regimen for MM. His renal function was monitored closely along with donor-specific antibody to assess for risk of graft rejection. His renal function remained stable with minimal proteinuria and negative donor-specific antibody during the treatment course.

Erectile dysfunction and coronary artery calcification in incident dialysis patients.

PURPOSE: Erectile dysfunction, which has been associated with mortality in the general population, is common in individuals on hemodialysis. Our aim was to determine the relationship between erectile dysfunction, coronary artery calcification and mortality in incident hemodialysis patients. MATERIALS AND METHODS: A prospective cohort of incident adult dialysis patients with no history of coronary artery disease underwent coronary artery calcification measurement by ECG-triggered multi-slice computed tomography (MSCT) scan at baseline and at least 12 months later. Erectile dysfunction was determined using the 15-item validated International Index of Erectile Function (IIEF-15) questionnaire. RESULTS: Erectile dysfunction was prevalent in 83% of patients, with 43% classified as severe erectile dysfunction, 22.4% as moderate erectile dysfunction, and 17.2% as mild erectile dysfunction. The median (IQR) coronary artery calcification score was 43.4 (0.25-353.8) for those with erectile dysfunction and 0 (0-0) for those without erectile dysfunction (p = 0.007). More than half (55.6%) of the patients with erectile dysfunction experienced progression of coronary artery calcification compared to 14.3% of patients without erectile dysfunction (p = 0.05). Mortality was 21% during an average follow-up of 5.2 (1.3) years. Twenty-three percent of patients with erectile dysfunction died compared to 10% of people without erectile dysfunction (p = 0.4). Erectile dysfunction was not significantly associated with mortality [HR 1.2 (1.3), p = 0.87]. CONCLUSIONS: Erectile dysfunction is common in individuals who start dialysis. It is significantly associated with an increased coronary artery calcification score, however, it is not associated with increased mortality in incident dialysis patients with no history of coronary artery disease.

The Glomerular Disease Study and Trial Consortium: A Grassroots Initiative to Foster Collaboration and Innovation.

Glomerular kidney disorders account for a significant proportion of chronic kidney disease and end-stage renal disease worldwide. Nevertheless, major obstacles make breakthrough progress in diagnosis and cure an ongoing challenge. Here we report the creation of a "grassroots" initiative that aims to provide new opportunities for nephrologists, pathologists, basic and clinical scientists, patients, and industry partners to collaborate in the field of glomerular kidney disease. Members of the medical community, including trainees, nephrologists, and nephropathologists, can participate in the open-access, Web-based, multidisciplinary clinical video case conferences, which provide "peer-to-peer" exchange of clinical and pathological expertise combined with a formal didactic curriculum. Participants can also join other aspects of the broader initiative. These include the participation in a multisite research study to facilitate enrollment of patients into a longitudinal clinical data and biorepository for glomerular kidney disorders. Items included in this prospective registry include the following: an ontology-based patient medical history, which is regularly updated; interval collection and storage of blood and urine samples; DNA collection; and a contact registry for patients who wish to participate in clinical trials. Participating sites and external scientists can leverage access to the database to pursue genetic, biomarker, epidemiological, and observational clinical effectiveness studies. Patients can independently sign up for a supplementary contact registry to participate in clinical trials if eligible. The broad spectrum of activities within this initiative will foster closer collaboration among trainees, practicing nephrologists, pathologists, and researchers, and may help to overcome some of the barriers to progress in the field of glomerular kidney disease.

Bilateral pneumothoraces secondary to acupuncture therapy.

Acupuncture is becoming increasingly popular in the United States for a wide variety of uses, ranging from the treatment of chronic back pain to aiding in addiction therapy. As this form of complementary and alternative medicine becomes more prevalent in certain areas of the country, it is of paramount importance that the emergency physician be familiar with its methods and potential complications. In general, acupuncture is perceived as fairly safe. However, it is not without risks or side effects. In this case report, we discuss the history, methods, and common complications of acupuncture in the context of a patient who presented to the Emergency Department (ED) with bilateral pneumothoraces secondary to acupuncture therapy.

Developmental haemostasis. Impact for clinical haemostasis laboratories.

Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980's. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whether a current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to age-related changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.

Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial.

BACKGROUND: There is controversy regarding whether hypersensitivity to food proteins contributes to colic among breastfed infants. METHODS: A randomized, controlled trial of a low-allergen maternal diet was conducted among exclusively breastfed infants presenting with colic. In the active arm, mothers excluded cow's milk, eggs, peanuts, tree nuts, wheat, soy, and fish from their diet; mothers in the control group continued to consume these foods. Outcomes were assessed after 7 days, as the change in cry/fuss duration over 48 hours, with validated charts. The primary end point was a reduction in cry/fuss duration of > or =25% from baseline. Mothers also assessed the responses to diet with categorical and visual analog scales. RESULTS: Of 107 infants, 90 completed the trial (mean age: 5.7 weeks; range: 2.9-8.6 weeks; 54 male infants). Infants in both groups presented with significant distress (geometric mean: low-allergen group: 690 minutes per 48 hours; control group: 631 minutes per 48 hours). In follow-up assessments on days 8 and 9, there were significantly more responders in the low-allergen group (74% vs 37%), ie, an absolute risk reduction of 37% (95% confidence interval: 18-56%). Cry/fuss duration per 48 hours was reduced by a substantially greater amount in the low-allergen group; the adjusted geometric mean ratio was 0.79 (95% confidence interval: 0.63-0.97), ie, an average reduction of 21% (95% confidence interval: 3-37%). Mothers' subjective assessments of the responses to diet indicated little difference between the groups. CONCLUSION: Exclusion of allergenic foods from the maternal diet was associated with a reduction in distressed behavior among breastfed infants with colic presenting in the first 6 weeks of life.

Intramolecular general acid catalysis of phosphate transfer. nucleophilic attack by oxyanions on the PO3 2- group.

Phosphate transfer from the 8-dimethylammonium-naphthyl-1-phosphate monoanion 4m to water and to a range of nucleophiles shows general acid catalysis by the neighboring NH(+) group, through the strong intramolecular hydrogen bond. Reactivity is insensitive to the charge on the nucleophile, so that fluoride and oxyanions displace dimethylaminonaphthol from the PO3(2-) group as effectively as do amines of the same basicity. Reactivity is (predictably) relatively insensitive to the basicity of the nucleophile and to the alpha-effect. A strong intramolecular hydrogen bond is present in the product, but also in the reactant, as evidenced by major perturbations in the pK(a)'s of the phosphate and dimethylamino groups, to 3.94 and 9.31, respectively, and by ab initio calculations. Rate accelerations are of the order of 10(6)-fold despite this stabilization: the strength of the hydrogen bond is evidently significantly enhanced in the transition state. The evidence suggests that it also depends remarkably strongly on the degree of ionization of the reacting phosphate group and will be significantly reduced for the neutral PO(OH)2 group. Thus, the hydrolysis of the substrate cation 4+ shows a correspondingly greater, >10(8)-fold acceleration.