Filter clotting with continuous renal replacement therapy in COVID-19.

Coronavirus disease 2019 (COVID-19) appears to be associated with increased arterial and venous thromboembolic disease. These presumed abnormalities in hemostasis have been associated with filter clotting during continuous renal replacement therapy (CRRT). We aimed to characterize the burden of CRRT filter clotting in COVID-19 infection and to describe a CRRT anticoagulation protocol that used anti-factor Xa levels for systemic heparin dosing. Multi-center study of consecutive patients with COVID-19 receiving CRRT. Primary outcome was CRRT filter loss. Sixty-five patients were analyzed, including 17 using an anti-factor Xa protocol to guide systemic heparin dosing. Fifty-four out of 65 patients (83%) lost at least one filter. Median first filter survival time was 6.5 [2.5, 33.5] h. There was no difference in first or second filter loss between the anti-Xa protocol and standard of care anticoagulation groups, however fewer patients lost their third filter in the protocolized group (55% vs. 93%) resulting in a longer median third filter survival time (24 [15.1, 54.2] vs. 17.3 [9.5, 35.1] h, p = 0.04). The rate of CRRT filter loss is high in COVID-19 infection. An anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels is reasonable approach to anticoagulation in this population.

American College of Foot and Ankle Surgeons Clinical Consensus Statement: Appropriate Clinical Management of Adult-Acquired Flatfoot Deformity.

This clinical consensus statement of the American College of Foot and Ankle Surgeons focuses on the highly debated subject of the management of adult flatfoot (AAFD). In developing this statement, the AAFD consensus statement panel attempted to address the most relevant issues facing the foot and ankle surgeon today, using the best evidence-based literature available. The panel created and researched 16 statements and generated opinions on the appropriateness of the statements. The results of the research on this topic and the opinions of the panel are presented here.

Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents.

UNLABELLED: Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events. CONCLUSION: SVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.

Optimal management of bone mineral disorders in chronic kidney disease and end stage renal disease.

PURPOSE OF REVIEW: The review summarizes recent studies on chronic kidney disease-mineral bone disorders, with a focus on new developments in disease management. RECENT FINDINGS: The term chronic kidney disease-mineral bone disorder has come to describe an increasingly complex network of alterations in minerals and skeletal disorders that contribute to the significant cardiovascular morbidity and mortality seen in patients with chronic kidney disease and end stage renal disease. Clinical studies continue to suggest associations with clinical outcomes, yet current clinical trials have failed to support causality. Variability in practice exists as current guidelines for management of mineral bone disorders are often based on weak evidence. Recent studies implicate novel pathways for therapeutic intervention in clinical trials. SUMMARY: Mineral bone disorders in chronic kidney disease arise from alterations in a number of molecules in an increasingly complex physiological network interconnecting bone and the cardiovascular system. Despite extensive associations with improved outcomes in a number of molecules, clinical trials have yet to prove causality and there is an absence of new therapies available to improve patient outcomes. Additional clinical trials that can incorporate the complexity of mineral bone disorders, and with the ability to intervene on more than one pathway, are needed to advance patient care.

Clinical predictors of diagnostic testing utility in the initial evaluation of chronic kidney disease.

AIM: No evidence-based approach to the evaluation of CKD has been established. We sought to identify clinical criteria to guide a rational diagnostic approach for the initial evaluation of CKD. METHODS: We conducted a retrospective cohort study of 1487 patients presenting for initial evaluation of CKD over 3 years (1/2010-1/2013) to academic nephrology clinics. We utilized the electronic medical record to determine tests ordered, abnormal results and testing that affected diagnosis and/or management. Diagnostic and management yield of testing was defined as the percentage of tests that affected diagnosis and/or management. High yield for a given test was defined as an increased likelihood of the test affecting diagnosis and/or management. RESULTS: We identified clinical criteria predictive of high yield for paraprotein-related testing (one of the following: history of monoclonal disease, high risk of CKD progression, hypercalcemia or haemoglobin < 10.6), and clinical criteria predictive of high yield for glomerulonephritis testing (one of the following: abnormal urine sediment, 3+ or greater hematuria or proteinuria > 500 mg/gm). A prior history of hydronephrosis and renal artery stenosis was predictive of high yield of abnormal renal ultrasound. Higher yield of testing was associated with higher risk progression categories for ANA, SPEP, urine sediment, calcium, PTH, haemoglobin, iron and ferritin. We estimate that initial CKD evaluation costs range from $28 to $109 million/year in US-Medicare expenditure. CONCLUSION: Numerous tests without significant clinical utility are obtained in initial CKD evaluation. Identifying criteria that can guide diagnostic testing may lead to a more informed and cost-effective approach to evaluation.

A pragmatic approach to selective genetic testing in kidney transplant candidates.

Introduction: Advances in the field of genetic testing have spurred its use in transplantation. Potential benefits of genetic testing in transplant nephrology include diagnosis, treatment, risk stratification of recurrent disease, and risk stratification in potential donors. However, it is unclear how to best apply genetic testing in this population to maximize its yield. We describe our transplant center's approach to selective genetic testing as part of kidney transplant candidate and donor evaluation. Methods: Transplant recipient candidates were tested if they had a history of ESRD at age <50, primary FSGS, complement-mediated or unknown etiology of kidney disease, or had a family history of kidney disease. Donors were tested if age <35, were related to their potential recipients with known genetic susceptibility or had a first-degree relative with a history of kidney disease of unknown etiology. A targeted NGS gene panel of 385 genes was used. Clinical implications and downstream effects were monitored. Results: Over 30% of recipients tested within the established criteria were positive for a pathogenic variant. The most common pathogenic variants were APOL1 high-risk genotypes as well as collagen 4-alpha-3, -4 and -5. Donor testing done according to our inclusion criteria resulted in about 12% yield. Positive test results in recipients helped with stratification of the risk of recurrent disease. Positive test results in potential donors guided informed decisions on when not to move forward with a donation. Discussion: Integrating targeted panel genetic testing into a kidney transplant clinic in conjunction with a selective criteria for testing donors and recipients ensured a reasonable diagnostic yield. The results had implications on clinical management, risk stratification and in some cases were instrumental in directing downstream changes including when to stop the evaluation process. Given the impact on management and transplant decisions, we advocate for the widespread use of genetic testing in selected individuals undergoing transplant evaluation and donation who meet pre-defined criteria.

Video Images about Decisions for Ethical Outcomes in Kidney Disease (VIDEO-KD): the study protocol for a multi-centre randomised controlled trial.

INTRODUCTION: Older patients with advanced chronic kidney disease (CKD) often are inadequately prepared to make informed decisions about treatments including dialysis and cardiopulmonary resuscitation. Further, evidence shows that patients with advanced CKD do not commonly engage in advance care planning (ACP), may suffer from poor quality of life, and may be exposed to end-of-life care that is not concordant with their goals. We aim to study the effectiveness of a video intervention on ACP, treatment preferences and other patient-reported outcomes. METHODS AND ANALYSIS: The Video Images about Decisions for Ethical Outcomes in Kidney Disease trial is a multi-centre randomised controlled trial that will test the effectiveness of an intervention that includes a CKD-related video decision aid followed by recording personal video declarations about goals of care and treatment preferences in older adults with advancing CKD. We aim to enrol 600 patients over 5 years at 10 sites. ETHICS AND DISSEMINATION: Regulatory and ethical aspects of this trial include a single Institutional Review Board mechanism for approval, data use agreements among sites, and a Data Safety and Monitoring Board. We intend to disseminate findings at national meetings and publish our results. TRIAL REGISTRATION NUMBER: NCT04347629.

Assessment of Interobserver Reliability of Nephrologist Examination of Urine Sediment.

Importance: Urine sediment microscopy is commonly performed during the evaluation of kidney disease. Interobserver reliability of nephrologists' urine sediment examination has not been well studied. Objective: Assess interobserver reliability of the urine sediment examination. Design, Setting, and Participants: In this diagnostic test study, urine samples were prospectively collected from a convenience sample of adult patients from an academic hospital in the United States undergoing kidney biopsy from July 11, 2018, to March 20, 2019. Digital images and videos of urine sediment findings were captured using a bright-field microscope. These images and videos along with urine dipstick results were incorporated in online surveys and sent to expert nephrologists at 15 US teaching hospitals. They were asked to identify individual sediment findings and the most likely underlying disease process. Exposures: Urine dipstick results and urine sediment images from patients undergoing native kidney biopsy. Main Outcomes and Measures: Interobserver reliability of urine sediment microscopy findings estimated by overall percent agreement and Fleiss κ coefficients. Secondary outcomes included concordance of diagnoses suspected by nephrologists with corresponding kidney biopsy results. Results: In total, 10 surveys from 10 patients containing 76 study questions on individual features were sent to 21 nephrologists, 14 (67%) of whom completed them all. Their combined 1064 responses were analyzed. Overall percent agreement for casts was an estimated 59% (95% CI, 50%-69%), κ = 0.52 (95% CI, 0.42-0.62). For other sediment findings, overall percent agreement was an estimated 69% (95% CI, 61%-77%), κ = 0.65 (95% CI, 0.56-0.73). The κ estimates ranged from 0.13 (95% CI, 0.10-0.17) for mixed cellular casts to 0.90 (95% CI, 0.87-0.94) for squamous epithelial cells. Conclusions and Relevance: In this study, substantial variability occurred in the interpretation of urine sediment findings, even among expert nephrologists. Educational or technological innovations may help improve the urine sediment as a diagnostic tool.

From Theory to Reality: Establishing a Successful Kidney Genetics Clinic in the Outpatient Setting.

Background: Genetic testing in nephrology is increasingly described in the literature and several groups have suggested significant clinical benefit. However, studies to date have described experience from established genetic testing centers or from externally funded research programs. Methods: We established a de novo kidney genetics clinic within an academic adult general nephrology practice. Key features of this effort included a pipeline for internal referrals, flexible scheduling, close coordination between the nephrologist and a genetic counselor, and utilization of commercial panel-based testing. Over the first year, we examined the outcomes of genetic testing, the time to return of genetic testing, and out-of-pocket cost to patients. Results: Thirty patients were referred and 23 were evaluated over the course of five clinic sessions. Nineteen patients underwent genetic testing with new diagnoses in nine patients (47%), inconclusive results in three patients (16%), and clearance for kidney donation in two patients (11%). On average, return of genetic results occurred 55 days (range 9-174 days) from the day of sample submission and the average out-of-pocket cost to patients was $155 (range $0-$1623). Conclusions: We established a kidney genetics clinic, without a pre-existing genetics infrastructure or dedicated research funding, that identified a new diagnosis in approximately 50% of patients tested. This study provides a clinical practice model for successfully incorporating genetic testing into ambulatory nephrology care with minimal capital investment and limited financial effect on patients.

Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats.

We investigated on the mechanism responsible for the reduced ATP-sensitive K(+)(K(ATP)) channel activity recorded from skeletal muscle of K(+)-depleted rats. Patch-clamp and gene expression measurements of K(ATP) channel subunits were performed. A down-regulation of the K(ATP) channel subunits Kir6.2(-70%) and SUR2A(-46%) in skeletal muscles of K(+)-depleted rats but no changes in the expression of Kir6.1, SUR1 and SUR2B subunits were observed. A reduced K(ATP) channel currents of -69.5% in K(+)-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the K(ATP) channels of normokalaemic and K(+)-depleted rats but reduced efficacy in K(+)-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated K(ATP) channels in normokalaemic and K(+)-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced K(ATP) channel activity in K(+)-depleted rats. The lower expression of SUR2A explains the reduced efficacy of cromakalim; preserved SUR1 expression accounts for the efficacy of diazoxide. Kir6.2/SUR2A deficiency is associated with impaired muscle function in K(+)-depleted rats and in hypoPP.

Ectopic germinal center and megalin defect in primary Sjogren syndrome with renal Fanconi syndrome.

BACKGROUND: This study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression. METHOD: Clinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression. RESULTS: Patients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21+ follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients. CONCLUSION: We report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers.

KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome.

BACKGROUND: Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene. METHODS AND RESULTS: The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. CONCLUSIONS: We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases.

Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.

BACKGROUND: In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS: The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS: KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

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.

An improved canine genome and a comprehensive catalogue of coding genes and non-coding transcripts.

The domestic dog, Canis familiaris, is a well-established model system for mapping trait and disease loci. While the original draft sequence was of good quality, gaps were abundant particularly in promoter regions of the genome, negatively impacting the annotation and study of candidate genes. Here, we present an improved genome build, canFam3.1, which includes 85 MB of novel sequence and now covers 99.8% of the euchromatic portion of the genome. We also present multiple RNA-Sequencing data sets from 10 different canine tissues to catalog ∼175,000 expressed loci. While about 90% of the coding genes previously annotated by EnsEMBL have measurable expression in at least one sample, the number of transcript isoforms detected by our data expands the EnsEMBL annotations by a factor of four. Syntenic comparison with the human genome revealed an additional ∼3,000 loci that are characterized as protein coding in human and were also expressed in the dog, suggesting that those were previously not annotated in the EnsEMBL canine gene set. In addition to ∼20,700 high-confidence protein coding loci, we found ∼4,600 antisense transcripts overlapping exons of protein coding genes, ∼7,200 intergenic multi-exon transcripts without coding potential, likely candidates for long intergenic non-coding RNAs (lincRNAs) and ∼11,000 transcripts were reported by two different library construction methods but did not fit any of the above categories. Of the lincRNAs, about 6,000 have no annotated orthologs in human or mouse. Functional analysis of two novel transcripts with shRNA in a mouse kidney cell line altered cell morphology and motility. All in all, we provide a much-improved annotation of the canine genome and suggest regulatory functions for several of the novel non-coding transcripts.

Thorough investigation of a canine autoinflammatory disease (AID) confirms one main risk locus and suggests a modifier locus for amyloidosis.

Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p<2.6×10(-8)) from each analysis showed that one haplotypic pair (H13-11) was present in the majority of AID individuals, implicating this as a shared risk factor for all phenotypes. We also noted that a genetic signature (F ST) distinguishing the phenotypic extremes of the breed specific Chinese Shar-Pei thick and wrinkled skin, flanked the chromosome 13 AID locus; suggesting that breed development and differentiation has played a parallel role in the genetics of breed fitness. Intriguingly, a potential modifier locus for amyloidosis was revealed on chromosome 14, and an investigation of candidate genes from both this and the chromosome 13 regions revealed significant (p<0.05) renal differential expression in four genes previously implicated in kidney or immune health (AOAH, ELMO1, HAS2 and IL6). These results illustrate that phenotypic heterogeneity need not be a reflection of genetic heterogeneity, and that genetic modifiers of disease could be masked if syndromes were not first considered as individual clinical signs and then as a sum of their component parts.