The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease.

Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, transgenic mice expressing D2D3 protein developed progressive kidney disease marked by microalbuminuria, elevated serum creatinine, and glomerular hypertrophy. D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic ß cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored ß cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired ß cell proliferation and inhibited the bioenergetics of ß cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus.

Fluid assessment in dialysis patients by point-of-care magnetic relaxometry.

Magnetic resonance imaging (MRI) is a powerful diagnostic tool, but its use is restricted to the scanner suite. Here, we demonstrate that a bedside nuclear magnetic resonance (NMR) sensor can assess fluid status changes in individuals at a fraction of the time and cost compared to MRI. Our study recruited patients with end-stage renal disease (ESRD) who were regularly receiving hemodialysis treatments with intradialytic fluid removal as a model of volume overload and healthy controls as a model of euvolemia. Quantitative T 2 measurements of the lower leg of patients with ESRD immediately before and after dialysis were compared to those of euvolemic healthy controls using both a 0.28-T bedside single-voxel NMR sensor and a 1.5-T clinical MRI scanner. In the MRI data, we found that the first sign of fluid overload was an expanded muscle extracellular fluid (ECF) space, a finding undetectable at this stage using physical exam. A decrease in muscle ECF upon fluid removal was similarly detectable with both the bedside sensor and MRI. Bioimpedance measurements performed comparably to the bedside NMR sensor but were generally worse than MRI. These findings suggest that bedside NMR may be a useful method to identify fluid overload early in patients with ESRD and potentially other hypervolemic patient populations.

Characterization and Correction of Olfactory Deficits in Kidney Disease.

Patients with CKD suffer from food aversion, anorexia, and malnutrition. Although olfaction has a significant role in determining food flavor, our understanding of olfactory impairment and of the olfaction-nutrition axis in patients with kidney disease is limited. We quantified odor identification, odor threshold, and subjective odor perception in a cohort (n=161) comprising 36 participants with CKD, 100 participants with ESRD, and 25 controls. We investigated olfaction-nutrition associations in these participants and examined a novel intervention to improve olfaction in ESRD. The mean odor identification score was lower in patients with CKD (75.6%±13.1%; P=0.02) and ESRD (66.8%±15.1%; P<0.001) than in controls (83.6%±11.4%). Patients with ESRD exhibited higher odor threshold than the remaining participants exhibited. All groups had similar scores for subjective smell assessment. In multivariable adjusted analyses, kidney disease associated with increased odds of odor identification deficits (odds ratio, 4.80; 95% confidence interval, 1.94 to 11.89). A reduction in odor identification score was associated with higher subjective global assessment score and lower serum total cholesterol, LDL cholesterol, and albumin concentrations. We found no associations between odor threshold and nutritional parameters. In a proof of concept, 6-week, open-label clinical trial, intranasal theophylline (an epithelial membrane transport and proton secretion activator) increased odor identification score in five out of seven (71%) patients with ESRD. In conclusion, patients with kidney disease have olfactory deficits that may influence their nutritional status. Our preliminary results regarding olfactory improvement using intranasal theophylline warrant confirmation in a randomized controlled trial.

Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy.

Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus-like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies.

Calciphylaxis in peritoneal dialysis patients: a single center cohort study.

BACKGROUND: Calciphylaxis is a rare but devastating condition in end-stage renal disease (ESRD) patients. Most research in the field of calciphylaxis is focused on hemodialysis (HD) patients; however, data on calciphylaxis incidence, risk factors, and mortality in peritoneal dialysis (PD) patients are limited. METHODS: In this cohort study, we examined data from adult patients who initiated PD for ESRD management at our institute's PD unit from January 2001 to December 2015. Associations with the development of calciphylaxis were examined for clinical, laboratory, and medication exposures. Incidence of calciphylaxis and mortality in PD patients who developed calciphylaxis were analyzed. Treatments administered to treat calciphylaxis in PD patients were summarized. RESULTS: In this cohort of 63 patients, 7 patients developed calciphylaxis (incidence rate: 9.0 per 1,000 patient-years). Median age of PD patients who developed calciphylaxis was 50 years, 57% were white, 71% females, and 71% were previously on HD. Female sex, obesity, HD as a prior dialysis modality, recurrent hypotension, elevated time-averaged serum phosphorous levels, reduced time-averaged serum albumin levels, and warfarin therapy were associated with increased calciphylaxis risk in univariate logistic regression analyses. Intravenous sodium thiosulfate was administered in 57% of PD patients who developed calciphylaxis. One-year mortality in PD patients who developed calciphylaxis was 71% despite multimodal treatment including sodium thiosulfate, hyperbaric oxygen, cinacalcet, and wound debridement. CONCLUSION: Calciphylaxis is a rare but frequently fatal condition in PD patients. Our study provides critical early insights into calciphylaxis incidence, risk factors, and prognosis in PD patients. Sample size and characteristics of patients included in our study limit generalizability to overall PD population and warrant examination in larger independent studies.

Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations. Although the approval of new therapies includes only one agent in 50 years, a number of promising new drugs are in development. Lupus nephritis is a dreaded complication of SLE as it is associated with significant morbidity and mortality. Advancing the treatment of lupus nephritis requires well-designed clinical trials and this can be challenging in SLE. The major obstacles involve identifying the correct population of patients to enroll and ensuring that a clinically appropriate and patient-centered endpoint is being measured. In this review, we will first discuss the clinical utility of endpoints chosen to represent lupus nephritis in global disease activity scales. Second, we will review completed and active trials focused on lupus nephritis and discuss the endpoints chosen. There are many important lessons to be learned from existing assessment tools and clinical trials. Reviewing these points will help ensure that future efforts will yield meaningful disease activity measures and well-designed clinical trials to advance our understanding of lupus management.

Bleeding complications of native kidney biopsy: a systematic review and meta-analysis.

BACKGROUND: Kidney biopsy provides important information for nephrologists, but the risk of complications has not been systematically described. STUDY DESIGN: Meta-analysis of randomized controlled trials and prospective or retrospective observational studies. SETTING & POPULATION: Adults undergoing native kidney biopsy in an inpatient or outpatient setting. SELECTION CRITERIA FOR STUDIES: MEDLINE indexed studies from January 1980 through June 2011; sample size of 50 or more. INTERVENTION: Native kidney biopsy with automated biopsy device and real-time ultrasonographic guidance. OUTCOMES: Macroscopic hematuria and erythrocyte transfusion rates and factors associated with these outcomes. RESULTS: 34 studies of 9,474 biopsies met inclusion criteria. The rate of macroscopic hematuria was 3.5% (95% CI, 2.2%-5.1%), and erythrocyte transfusion was 0.9% (95% CI, 0.4%-1.5%). Significantly higher rates of transfusion were seen with the following: 14-gauge compared with smaller needles (2.1% vs 0.5%; P = 0.009), studies with mean serum creatinine level ≥2.0 mg/dL (2.1% vs 0.4%; P = 0.02), ≥50% women (1.9% vs 0.6%; P = 0.03), and ≥10% of biopsies for acute kidney injury (1.1% vs 0.04%; P < 0.001). Higher transfusion rates also were observed in studies with a mean age of 40 years or older (1.0% vs 0.2%; P = 0.2) and mean systolic blood pressure ≥130 mm Hg (1.4% vs 0.1%; P = 0.09). Similar relationships were noted for the macroscopic hematuria rate with the same predictors, but none was statistically significant. LIMITATIONS: Publication bias, few randomized controlled trials, and missing data. CONCLUSIONS: Native kidney biopsy using automated biopsy devices and real-time ultrasonography is associated with a relatively small risk of macroscopic hematuria and erythrocyte transfusion requirement. Using smaller gauge needles may lower complication rates. Patient selection may affect outcome because studies with higher serum creatinine levels, more women, and higher rates of acute kidney injury had higher complication rates. Future studies should further evaluate risk factors for complications.

A prospective global measure, the Punum Ladder, provides more valid assessments of quality of life than a retrospective transition measure.

OBJECTIVES: We assessed the reliability and validity of two measures of change, one retrospective (the Global Rating of Change Scale [GRCS]) and one prospective (the Punum Ladder), and the relative utility of the two methods of assessing change and establishing the minimal important difference (MID) of the Cough Quality of Life Questionnaire (CQLQ), a reliable and valid cough-specific quality-of-life (QoL) instrument. STUDY DESIGN AND SETTING: A prospective, longitudinal study assessing the change in cough-related QoL over 6 months in participants with chronic cough was carried out in a tertiary care cough clinic. Before seeing a physician, subjects completed eight Punum Ladders and the CQLQ. At 1 and 6 months, eight Punum Ladders, the CQLQ, and seven GRCSs were completed. Punum Ladders and GRCSs were psychometrically tested, and MIDs were calculated. RESULTS: Reliability and validity of GRCSs and Punum Ladders were acceptable. However, closer analysis of the relation between change scores and CQLQ pretest and posttest scores showed that the GRCS was only related to patient's present state, whereas the Punum Ladder was associated with both initial and present states. This compromises the validity of the GRCS. Crosstab comparisons revealed that GRCS ratings made more liberal estimates of change in the CQLQ than the Punum Ladder; this is reflected in their respective MIDs (10.58+/-10.63 vs. 21.89+/-15.38). CONCLUSION: The prospective Punum Ladder is likely to be more useful, because it reflects the actual change in QoL over time in a less biased and more accurate way than the retrospective GRCS.

Management of Lyme disease.

It has been 30 years since Lyme disease was first described in a cohort of patients from Connecticut. An understanding of disease transmission, clinical manifestations and prevention strategies has been established. With the number of new cases increasing each year, it is important that clinicians are aware of the available treatment options. Most patients respond well to a course of treatment with a recommended antibiotic; however, for those patients who develop post-Lyme disease syndrome, the management is unclear. This review provides an overview of Lyme disease and the recommended treatment options available to physicians.

Concurrent task performance enhances low-level visuomotor learning.

Visuomotor association learning involves learning to make a motor response to an arbitrary visual stimulus. This learning is essential for visual search and discrimination performance and is reliant upon a well-defined neural circuit in the brain that includes the prefrontal cortex and the hippocampal formation. In the present study, we investigated the possible role of attentional processes during such learning using dual-task interference. A motor, verbal, or perceptual concurrent task was performed during the learning/training block of a simple visual discrimination task. Contrary to expectation, the dual-task groups showed improved learning and learning-dependent performance compared with untrained control and non-dual-task trained groups. A second experiment revealed that this effect did not appear to be due to increased arousal level; the inclusion of alerting tones during learning did not result in facilitation. These findings suggest that the engagement of attention, but not arousal, during the acquisition of a visuomotor association can facilitate this learning and its expression.

Strategies for primary and secondary prevention of Lyme disease.

Lyme disease (borreliosis) incidence continues to increase despite a growing knowledge of primary and secondary prevention strategies. Primary prevention aims to reduce the risk of tick exposure and thereby decrease the incidence of new Lyme disease cases. Secondary prevention targets the development of disease or reduces disease severity among people who have been bitten by infected ticks. Numerous prevention strategies are available, and although they vary in cost, acceptability and effectiveness, uptake has been universally poor. Research in areas where Lyme disease is endemic has demonstrated that despite adequate knowledge about its symptoms and transmission, many people do not perform behaviors to reduce their risk of infection. New prevention strategies should aim to increase people's confidence in their ability to carry out preventive behaviors, raise awareness of desirable outcomes, and aid in the realization that the necessary skills and resources are available for preventive measures to be taken. In this article we evaluate the prevention and treatment strategies for Lyme disease, and discuss how these strategies can be implemented effectively. As many patients with Lyme disease develop arthritis and are referred to rheumatologists it is important that these health-care providers can educate patients about disease-prevention strategies.

Screening for frailty among seniors in clinical practice.

The normal course of aging is associated with gradual declines in a number of functional abilities. Patients who are at high risk of functional decline are described as frail or vulnerable. A screening tool to identify such patients is needed, as it has been shown that intervention can delay the onset and/or slow the progression of functional decline. This Review describes the methods currently available for nonspecialist evaluation of aging individuals, including behavioral, interview and questionnaire assessments. Such assessments can be undertaken during routine physician visits. In recognition of the time pressures on physicians, this article focuses on those measurements that are fairly comprehensive yet concise, easy to administer in an office setting, and available in English.

Progression of Parkinson's disease following thalamic deep brain stimulation for tremor.

We assessed the long-term effect of thalamic deep brain stimulation (DBS) on motor symptoms and progression of Parkinson's disease (PD) in PD patients treated for resting and postural/action tremor. Thalamic DBS was performed in 17 patients with treatment-resistant resting and postural/action tremor. Nine patients were available for follow-up examination a mean of 5.5 years after surgery. Three had tremor-dominant PD. DBS produced marked improvement in resting and postural/action tremor in target upper extremity in all 9 patients, which persisted unchanged at the time of the last follow-up visit 5.5 years after surgery. PD severity with DBS 'on' and 'off' 1 year after surgery was compared to PD severity at the last follow-up visit using UPDRS (Unified Parkinson's Disease Rating Scale) III motor scores and individual motor item subscores. Patients were tested while on medication. There was no significant worsening of tremor, rigidity, speech, postural stability, gait, or axial bradykinesia with DBS either on or off at the last follow-up visit compared to the 12-month visit. UPDRS III motor scores were unchanged. However, global assessment of PD progression and increased mean L-dopa dose and L-dopa equivalent daily dose at the time of last follow-up visit indicated that a progression of PD had occurred.