American Board of Internal Medicine Nephrology Procedure Requirements for Initial Certification: Time for a Change and Pursuing Consensus in the Nephrology Community.

In 1988, the American Board of Internal Medicine (ABIM) defined essential procedural skills in nephrology, and candidates for ABIM certification were required to present evidence of possessing the skills necessary for placement of temporary dialysis vascular access, hemodialysis, peritoneal dialysis, and percutaneous renal biopsy. In 1996, continuous renal replacement therapy was added to the list of nephrology requirements. These procedure requirements have not been modified since 1996 while the practice of nephrology has changed dramatically. In March 2021, the ABIM Nephrology Board embarked on a policy journey to revise the procedure requirements for nephrology certification. With the guidance of nephrology diplomates, training program directors, professional and patient organizations, and other stakeholders, the ABIM Nephrology Board revised the procedure requirements to reflect current practice and national priorities. The approved changes include the Opportunity to Train standard for placement of temporary dialysis catheters, percutaneous kidney biopsies, and home hemodialysis which better reflects the current state of training in most training programs, and the new requirements for home dialysis therapies training will align with the national priority to address the underuse of home dialysis therapies. This perspective details the ABIM process for considering changes to the certification procedure requirements and how ABIM collaborated with the larger nephrology community in considering revisions and additions to these requirements.

Existence of common fuzzy fixed points via fuzzy F-contractions in b-metric spaces.

The main goal of this study is to establish common fuzzy fixed points in the context of complete b-metric spaces for a pair of fuzzy mappings that satisfy F-contractions. To strengthen the validity of the derived results, non-trivial examples are provided to substantiate the conclusions. Moreover, prior discoveries have been drawn as logical extensions from pertinent literature. Our findings are further reinforced and integrated by the numerous implications that this technique has in the literature. Using fixed point techniques to approximate the solutions of differential and integral equations is very useful. Specifically, in order to enhance the validity of our findings, the existence result of the system of non-linear Fredholm integral equations of second-kind is incorporated as an application.

Correction: Identification and In-Silico study of non-synonymous functional SNPs in the human SCN9A gene.

[This corrects the article DOI: 10.1371/journal.pone.0297367.].

Identification and In-Silico study of non-synonymous functional SNPs in the human SCN9A gene.

Single nucleotide polymorphisms are the most common form of DNA alterations at the level of a single nucleotide in the genomic sequence. Genome-wide association studies (GWAS) were carried to identify potential risk genes or genomic regions by screening for SNPs associated with disease. Recent studies have shown that SCN9A comprises the NaV1.7 subunit, Na+ channels have a gene encoding of 1988 amino acids arranged into 4 domains, all with 6 transmembrane regions, and are mainly found in dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons. Multiple forms of acute hypersensitivity conditions, such as primary erythermalgia, congenital analgesia, and paroxysmal pain syndrome have been linked to polymorphisms in the SCN9A gene. Under this study, we utilized a variety of computational tools to explore out nsSNPs that are potentially damaging to heath by modifying the structure or activity of the SCN9A protein. Over 14 potentially damaging and disease-causing nsSNPs (E1889D, L1802P, F1782V, D1778N, C1370Y, V1311M, Y1248H, F1237L, M936V, I929T, V877E, D743Y, C710W, D623H) were identified by a variety of algorithms, including SNPnexus, SNAP-2, PANTHER, PhD-SNP, SNP & GO, I-Mutant, and ConSurf. Homology modeling, structure validation, and protein-ligand interactions also were performed to confirm 5 notable substitutions (L1802P, F1782V, D1778N, V1311M, and M936V). Such nsSNPs may become the center of further studies into a variety of disorders brought by SCN9A dysfunction. Using in-silico strategies for assessing SCN9A genetic variations will aid in organizing large-scale investigations and developing targeted therapeutics for disorders linked to these variations.

Evaluation Evolution: Designing Optimal Evaluations to Enhance Learning in Nephrology Fellowship.

Evaluations serve as the backbone of any educational program and can be broadly divided into formative and summative evaluations. Formative evaluations are "just in time" evaluations focused on informing the learning process, whereas summative evaluations compare fellows to a preset standard to determine their readiness for unsupervised practice. In the nephrology fellowship programs, evaluations assess competence in the framework of ACGME Milestones 2.0. A variety of learning venues, evaluators, and tools should be incorporated into the measurement process. It is important to determine which milestones can be best assessed in each education venue to decrease the burden of assessment fatigue. Additionally, programs can diversify the evaluators to include nurses, medical students, peers, and program coordinators in addition to faculty to provide a well-rounded assessment of the fellows and share the assessment burden. Lastly, the evaluation data should be presented to fellows in a format where it can inform goal setting. The evaluation system needs to evolve along with the changes being made in curriculum design. This will help to make fellowship learning effective and efficient.

What happens after the kidney biopsy? The findings nephrologists should know.

BACKGROUND: Percutaneous kidney biopsies are important tools for the diagnosis of kidney diseases. Nephrologists must be familiar with the expected complications of the procedure to provide an adequate informed consent. Here, we present a quality improvement analysis that reviews the complication rate of percutaneous kidney biopsies performed over a 2-year period by nephrologists at a single center, and that tabulates the nature and timing of these events. METHODS: From a single center cohort, pre- and post-biopsy anthropomorphic and clinical measurements were collected. Post-biopsy complications were tracked and sorted into either major or minor complications. Statistical tests were used to analyze complication incidence across the pre- and post-biopsy measurements obtained. RESULTS: Of the 154 nephrologist-performed percutaneous native kidney biopsies, 2 biopsies (1.3%) were found to result in a major complication. Both major complications were detected within 4 hours of the biopsy. Analysis of the pre-biopsy and post-biopsy measurements found that the proportion of complications was higher in patients with hematuria prior to biopsy. It was also found that patients with complications were statistically younger and had fewer comorbidities. Under univariable analysis, older age was associated with a lower incidence rate ratio for complications. However, no pre-or-post biopsy measurement or characteristic had a statistically significant change in incidence rate ratio under multivariable analysis. CONCLUSIONS: Percutaneous kidney biopsies were found to be low risk when performed by nephrologists in this single center cohort. Consistent with past literature, life threatening major complications rarely occurred and were reliably identified within 4 hours of biopsy, suggesting that centers can consider reduced observation times without compromising patient safety. Minor complications, such as pain, were more likely to occur in younger, healthier patients, and in those with hematuria prior to biopsy. This extensive tabulation of all biopsy adverse events is the first of its kind and will be beneficial for nephrologists to inform discussions with patients about expectations and risk-benefit of this procedure.

Targeting Zero Infections in the Outpatient Dialysis Unit: Core Curriculum 2020.

Although overall mortality rates in dialysis patients have improved during the last decade or so, infections remain a leading cause of death, second only to cardiovascular disease. In addition, infections account for a major share of hospitalizations in this patient population. Receiving hemodialysis treatments in an outpatient dialysis facility significantly contributes to patients' risks for infection. In dialysis units, patient-to-patient transmission of viral pathogens such as hepatitis B virus, hepatitis C virus, and human immunodeficiency virus can occur; proper screening and vaccination of patients can decrease the risk for transmission. Strict adherence to hand hygiene, use of appropriate personal protective equipment, transmission-based precautions, and maintaining aseptic technique while connecting the access to the hemodialysis machine can substantially decrease the likelihood of bacterial infections. With an effective infection control program in place, infection prevention becomes part of the dialysis facility's culture and results in improved patient safety. In this installment of the Core Curriculum series, we highlight best practices that should be followed by health care workers in the dialysis unit and discuss the role of the medical director in promoting initiatives to reduce infection rates.

Gender differences in peritoneal dialysis initiation in the US end-stage renal disease population.

BACKGROUND: Overall, a disproportionately small number of end-stage renal disease (ESRD) patients start peritoneal dialysis (PD) in the United States compared to hemodialysis. Little is known about whether gender has an effect on the initial modality of renal replacement therapy utilized by patients; however, prior studies have demonstrated gender disparities in the diagnosis and treatment of various other health conditions, including kidney disease. METHODS: Using data from the United States Renal Data System (USRDS), we estimated the proportion of patients utilizing PD as their initial dialysis modality between 2000 and 2014, adjusting estimates to the mean value of all covariates and compared these estimates for women and men. RESULTS: We found that 7.9% of women and 7.5% of men used PD as their initial dialysis modality. The unadjusted odds ratio (OR) of women initiating PD as their initial modality compared to men was 1.04 (95% CI 1.02-1.05, p < 0.001). After adjustment for age, race, ethnicity, cause of ESRD, number of comorbidities, income, employment status, and timing of referral to nephrology, the difference was even more significant, with women being 12% (OR 1.12, CI 1.10-1.14, p < 0.001) more likely to initiate PD than men. However, within different subgroups, older women and women with higher number of comorbidities were less likely to be on PD than their male counterparts. CONCLUSIONS: Our results indicate that gender plays a role in the initial dialysis modality used by patients and providers should be cognizant of these gender differences. Further studies are needed to ascertain the cause of this observed difference.

Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A.

Nitric oxide (NO) is implicated in several biological processes, including cancer progression. At low concentrations, it promotes cell survival and tumor progression, and at high concentrations it causes apoptosis and cell death. Until now, the impact of NO donors has not been investigated on human endometrial tumors. Four cancer cell lines were exposed to different concentrations of DETA/NO for 24 to 120 h. The effects of DETA/NO on cell proliferation and invasion were determined utilizing MTS and Boyden chamber assays, respectively. The DETA/NO induced a dose and time-dependent reduction in cell viability by the activation of caspase-3 and cell cycle arrest at the G0/G1 phase that was associated with the attenuated expression of cyclin-D1 and D3. Furthermore, the reduction in the amount of CD133-expressing cancer stem-like cell subpopulation was observed following DETA/NO treatment of cells, which was associated with a decreased expression of stem cell markers and attenuation of cell invasiveness. To understand the mechanisms by which DETA/NO elicits anti-cancer effects, RNA sequencing (RNA-seq) was used to ascertain alterations in the transcriptomes of human endometrial cancer cells. RNA-seq analysis revealed that 14 of the top 21 differentially expressed genes were upregulated and seven were downregulated in endometrial cancer cells with DETA/NO. The genes that were upregulated in all four cell lines with DETA/NO were the tumor suppressors Ras association domain family 1 isoform A (RASSF1) and Cyclin-dependent kinase inhibitor 1A (CDKN1A). The expression patterns of these genes were confirmed by Western blotting. Taken together, the results provide the first evidence in support of the anti-cancer effects of DETA/NO in endometrial cancer.

End-Stage Renal Disease Patients with Low Serum Albumin: Is Peritoneal Dialysis an Option?

Introduction:Low serum albumin is associated with high mortality in patients with end-stage renal disease (ESRD) on chronic dialysis. Clinicians are reluctant to offer peritoneal dialysis (PD) as an option for dialysis for patients with low serum albumin due to concerns of loss of albumin with PD, but evidence supporting differences in outcomes is limited. We evaluated mortality based on dialysis modality in patients with very low serum albumin (< 2.5 g/dL).Methods:We analyzed United States Renal Data System (USRDS) data from 2010 to 2015 to assess mortality by modality adjusted for age, sex, race, employment, number of comorbidities, and year of dialysis initiation.Results:Low serum albumin (< 2.5 g/dL) was present in 78,625 (19.9%) of 395,656 patients with ESRD on chronic dialysis. Patients with low serum albumin were less likely to use PD as their first modality than those with higher albumin (3.1% vs 10.9%; p < 0.001). Use of PD was associated with lower mortality compared with hemodialysis (HD) (hazard ratio [HR] = 0.88, 95% confidence interval [CI] 0.81 - 0.95, p < 0.05) in patients with low serum albumin. This difference was more pronounced in patients who had glomerulonephritis (HR = 0.72) or hypertension (HR = 0.81) than in those with end-stage renal disease (ESRD) due to diabetes mellitus or other causes.Conclusion:Peritoneal dialysis is less likely to be the first dialysis modality in patients with low serum albumin requiring dialysis. However, PD is associated with lower mortality than HD in patients with low serum albumin on dialysis. We recommend advocating the use of PD in patients with low serum albumin.

Improvement in Hyperphosphatemia Using Phosphate Education and Planning Talks.

OBJECTIVE: Hyperphosphatemia is a common complication in patients with end-stage renal disease on hemodialysis. The mainstay of phosphate management involves a low-phosphate diet and use of phosphate binders, yet these are often insufficient. This study was the first to use behavioral change techniques to encourage the use of phosphate binders and dietary modifications through a series of Phosphate Education and Planning (PEP) talks. DESIGN AND METHODS: A total of 46 hemodialysis patients with hyperphosphatemia were enrolled. All patients were eligible to receive a series of 4 talks, each with defined goals of the long-term management of serum phosphate levels. Qualitative data from the talks were gathered during each intervention, whereas serum phosphate was selected as an outcome measure. RESULTS: There was a modest improvement (-0.31 mg/dL) in the serum phosphate levels of the patients who received the entire PEP talk series. Furthermore, the most common self-identified barriers for patients were phosphate binder prescriptions not tailored to their eating routines and lack of resources for suitable dietary changes. CONCLUSIONS: The PEP talk series model is appropriate to manage persistent hyperphosphatemia despite usual management in outpatient dialysis unit by identifying patient-specific barriers and providing resources that can mitigate them. The strength of this model lies in using a multifaceted approach by applying both pharmacotherapy and dietary changes, along with behavioral change, to achieve lasting improvements in serum phosphate levels in hemodialysis patients with persistently elevated serum phosphate levels.

RNA interference screening identifies clathrin-B and cofilin-1 as mediators of MT1-MMP in endometrial cancer.

The matrix metalloproteinases (MMPs) are implicated in tumor invasion and metastasis. Given their multiple tumor promoting roles, MMPs are promising targets for the treatment of metastatic cancer. Using a siRNA library screen of 140 membrane trafficking genes, we identified 41 genes in HEC-1B and 36 in Ishikawa cancer cells that decreased metalloproteinases activity. The 16 genes common in both cancer cell lines that decreased MMPs activity are involved in cargo sorting, vesicle formation and vesicle recycling. The top two genes clathrin-B and cofilin-1 were chosen for post hoc functional studies. Higher expression of both genes was confirmed in cancer cells and knockdown with respective siRNAs inhibited their invasive potential and matrix metalloproteinases activity. Membrane Type 1- Matrix Metalloproteinase (MT1-MMP) is a master switch proteinase and regulator of invasion and metastasis. A marked decrease in MT1-MMP expression and activity was seen in clathrin-B and cofilin-1 knockdown cancer cells which was associated with a marked decreased expression of invadopodia formation proteins. Our results suggest that the decreased expression of clathrin-B and cofilin-1 decreases the expression of MT1-MMP and results in attenuation of MT1-MMP at the cell surface, thus inhibiting tumor cell invasion and metastasis.

Scutellaria baicalensis targets the hypoxia-inducible factor-1α and enhances cisplatin efficacy in ovarian cancer.

Hypoxia-inducible factor-1alpha (HIF-1α) is aberrantly upregulated in tumors and implicated in angiogenesis, metastasis, and drug resistance. Therefore, developing treatments that target HIF-1α may be a viable therapeutic approach. In Traditional Chinese Medicine (TCM), Scutellaria baicalensis (SB) is used for the treatment of cancer but the anti-cancer mechanisms are not known. We examined the effects of SB on HIF-1α expression in ovarian cancer (OC) cell lines grown under normoxic and hypoxic conditions. SB treatment attenuated HIF-1α expression in cancer cell lines. Treatment of cells with cycloheximide (CHX) reduced HIF-1α levels similar to cells treated with SB. Furthermore, SB-induced HIF-1α inhibition was abrogated by the proteasomal inhibitor MG132 and a lysosome inhibitor, chloroquine. Activation of PI3K/AKT and MAPK/ERK seen in OC cells was reduced with SB. Pretreatment of cells with LY294002 (phosphoinositide 3-kinase inhibitor) and PD98059 (mitogen-activated protein kinase inhibitor) reduced HIF-1α expression comparable to SB-treated cells. SB potentiated the anti-growth effects of cisplatin on OC cells by attenuating the expression of HIF-1α, ABCG1, and ABCG2. Taken together, the findings suggest that targeting HIF-1α with SB could be an effective treatment strategy for cancer and SB can improve the sensitivity of cancer cells to cisplatin, which is a major challenge in therapy for ovarian tumors.

Dialysis access procedure training for the nephrologist.

Historically, the placement and maintenance of dialysis access has been an integral part of nephrology training. However, in recent years, a big debate has ensued regarding whether this should be limited to trainees' understanding and counseling the patients regarding indications, alternatives, risks and possible complications of these procedures or should it actually involve more of a hands-on experience for the trainees. Some of the barriers in making these procedures a requirement across the board are the lack of standardization of procedural training across various training programs and the absence of consensus on what achieving competency in these procedures looks like. However, in the era of declining interest in nephrology, giving up "ownership" of nephrology procedures and increasing reliance on other sub specialties might be a deterrent in attracting residents to this field; we have to make a concerted effort to increase the exposure and opportunities for the trainees to perform these procedures. Moreover, we need to emphasize the implementation of a curriculum for nephrology fellows to evaluate access properly in order to decrease the burden of access related complications. Lastly, we need to continue working towards a more structured curriculum for a dedicated interventional nephrology fellowship for trainees who want to focus on procedures for their long-term career goals.

The viscoelastic response of electrospun poly(vinyl alcohol) mats.

Native biological tissues are viscoelastic materials that undergo time-dependent loading in vivo. It is therefore crucial to ensure that biomedical materials have a suitable viscoelastic response for a given application. In this study, the viscoelastic properties of electrospun poly(vinyl alcohol) are investigated using tensile load relaxation testing. A five-parameter generalised Maxwell constitutive model is found to characterise the experimental response. The effect of polymer concentration and electrospinning voltage on model parameters is investigated in detail. The stiffness coefficients for the relaxation process appear to be dependent on the electrospinning conditions used whereas the time constants remain relatively unchanged. It is also observed that the stiffness parameters are linearly correlated with the equilibrium modulus, indicating that a single underlying material property dictates the relaxation moduli. Lastly, it is found that the viscoelastic model parameters are not predicted by the fibre diameter. These results provide an important understanding in designing electrospun mats with desired time-dependent properties.

Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality.

BACKGROUND: Although hyperuricemia is common after orthotopic liver transplantation (OLT), its relationship to mortality, progressive kidney disease, or the development of end stage renal disease (ESRD) is not well-described. METHODS: Data from 304 patients undergoing OLT between 1996 and 2010 were used to assess the association of mean serum uric acid (UA) level in the 3-months post-OLT with mortality, doubling of creatinine, and ESRD incidence. Post-OLT survival to event outcomes according to UA level and eGFR was assessed using the Kaplan Meier method and multivariate Cox proportional hazards models. RESULTS: Mean UA level among the 204 patients with an eGFR level ≥60 ml/min/1.73 m2 was 6.4 mg/dl compared to 7.9 mg/dl among the 100 patients with eGFR <60 (p < 0.0001). During a median of 4.6 years of follow-up, mortality rate, doubling of creatinine, and ESRD incidence were 48.9, 278.2, and 20.7 per 1000 person-years, respectively. In the first 5 years of follow-up, elevated UA was associated with mortality (Hazard Ratio, HR = 1.7; p = 0.045). However, among those with eGFR ≥ 60, UA level did not predict mortality (HR = 1.0; p = 0.95), and among those with eGFR < 60, elevated UA was a strong predictor of mortality (HR = 3.7[1.1, 12.0]; p = 0.03). UA was not associated with ESRD, but was associated with doubling of creatinine among diabetics (HR = 2.2[1.1, 4.3]; p = 0.025). CONCLUSION: In this post-OLT cohort, hyperuricemia independently predicted mortality, particularly among patients with eGFR < 60, and predicted doubling of creatinine among diabetics.

Progesterone and calcitriol reduce invasive potential of endometrial cancer cells by targeting ARF6, NEDD9 and MT1-MMP.

Previously, we have demonstrated that progesterone and calcitriol synergistically inhibit growth of endometrial and ovarian cancer by enhancing apoptosis and causing cell cycle arrest. Metastasis is the main reason of mortality in cancer patients. Activation of ADP-Ribosylation Factor 6 (ARF6), Neural Precursor cell expressed Developmentally Downregulated 9 (NEDD9), and Membrane-Type-1 Matrix Metalloproteinase (MT1-MMP) have been implicated in promoting tumor growth and metastasis. We examined the effects of progesterone, calcitriol and progesterone-calcitriol combination on metastasis promoting proteins in endometrial cancer. Expression of ARF6, NEDD9, and MT1-MMP was enhanced in advanced-stage endometrial tumors and in cancer cell lines compared to normal tissues and immortalized EM-E6/E7-TERT endometrial epithelial cells. Knockdown of these proteins significantly inhibited the invasiveness of the cancer cells. The expression levels of all three proteins was reduced with progesterone and progesterone-calcitriol combination treatment, whereas calcitriol alone showed no effect on their expression but moderately decreased MT1-MMP activity. Fluorescence microscopy showed membrane expression of MT1-MMP in vehicle and calcitriol-treated endometrial cancer cells. However, progesterone and calcitriol-progesterone combination treatment revealed MT1-MMP in the cytoplasm. Furthermore, progesterone and calcitriol reduced the activity of MT1-MMP, MMP-9, and MMP-2. In addition, invadopodia regulatory proteins were attenuated in both progesterone and progesterone-calcitriol combination treated cells as well as in MT1-MMP knockdown cells. Thus, targeting the aberrant MT1-MMP signaling with progesterone-calcitriol may be a novel approach to impede MT1-MMP mediated cancer dissemination and may have therapeutic benefits for endometrial cancer patients.

Association of Pre-Transplant Dialysis Modality and Post-Transplant Outcomes: A Meta-Analysis.

♦ BACKGROUND: It remains unclear whether post-transplant outcomes differ according to the pre-transplant dialysis modality (peritoneal dialysis [PD] versus hemodialysis [HD]). We performed a meta-analysis of studies that assessed either post-transplant mortality, graft survival, or delayed graft function (DGF) in both PD and HD patients. ♦ METHODS: Two independent authors searched English-language literature from January 1, 1980, through August 31, 2014, national conference proceedings, and reference lists. We used combinations of terms related to dialysis (hemodialysis, peritoneal dialysis, or renal replacement therapy), kidney transplant, and outcomes. Studies were included if they measured any of the 3 post-transplant study outcomes in both pre-transplant HD and PD. ♦ RESULTS: A total of 16 studies were included in the final analysis. Of these, 6 studies reported adjusted hazard ratio for mortality, pooled adjusted risk ratio: 0.89 (95% confidence interval [CI] 0.82 - 0.97) in favor of PD (p = 0.006). The same 6 studies reported adjusted hazard ratio for graft survival, pooled adjusted risk ratio: 0.97 (95% CI 0.92 - 1.01, p = 0.16). A total of 13 studies reported unadjusted DGF. Pooled odds ratio: 0.5 (95% CI 0.41 - 0.63) in favor of PD (p < 0.005). Significant heterogeneity observed for all outcomes: I2 = 72.7%, I2 = 59.9%, and I2 = 66.8%, respectively. ♦ CONCLUSIONS: Based on these results, pre-transplant PD is associated with better post-transplant survival than HD. Pre-transplant PD was also associated with decreased risk for DGF compared with HD, although these results were unadjusted. There was no significant difference in graft survival between pre-transplant HD and PD. These results suggest that PD may be the preferred dialysis modality for patients expected to receive a transplant.

Multiple recurrences of anti-glomerular basement membrane disease with variable antibody detection: can the laboratory be trusted?

Anti-glomerular basement membrane (GBM) disease is commonly a monophasic illness. We present the case of multiple recurrences of anti-GBM disease with varying serum anti-GBM antibody findings. A 33-year-old female tobacco user presenting with hematuria was diagnosed with anti-GBM disease by renal biopsy. Five years later, she presented with alveolar hemorrhage and positive anti-GBM antibody. She presented a third time with alveolar hemorrhage but undetectable anti-GBM antibody. With each occurrence, symptoms resolved with plasmapheresis, intravenous methylprednisone and oral cyclophosphamide. The relationship between anti-GBM antibody findings and disease presentation is complex. Clinicians should be aware of the possibility of seronegative anti-GBM disease.