American Society of Nephrology Kidney Tutored Research and Education for Kidney Scholars (TREKS) Program: A 10-Year Interim Analysis.

In response to decreasing numbers of individuals entering into nephrology fellowships, the American Society of Nephrology launched Kidney Tutored Research and Education for Kidney Scholars (TREKS) to stimulate interest in nephrology among medical students, graduate students, and postdoctoral fellows. The program combines a 1-week intensive exposure to kidney physiology with a longitudinal mentorship program at the participants' home institutions. Ten years in, an analysis was conducted to assess its effectiveness. We surveyed participants to assess their opinions regarding nephrology before and after the course and followed them longitudinally to determine their career choices. TREKS applicants who were not selected to participate were used as a comparison group. Three hundred eighty-one people participated in the program, and 242 completed the survey. After TREKS, both medical students and graduate students showed increased interest in nephrology, with rank scores of 5.6±0.2 before to 7.5±0.1 after the course for medical students (mean±SD, n =189, P = 0.001) and 7.3±0.3 to 8.7±0.3 ( n =53, P = 0.001) for graduate students. In long-term follow-up, TREKS medical students chose a nephrology pipeline residency at a higher rate than medical students overall (57% versus 31%, P = 0.01) and TREKS applicants who did not participate (47% versus 31%, P = 0.04). Nephrology fellowship rates for these groups exceeded the general population but did not significantly differ between TREKS participants and applicants. Doctor of Philosophy students and postdoctoral TREKS participants had a higher rate of participation in nephrology research compared with TREKS applicants (66% versus 30%, P = 0.01). In summary, the American Society of Nephrology Kidney TREKS program has demonstrated that it can increase interest in nephrology in the short term and increase the number of individuals going into nephrology careers. This long-term effect is most evident in Doctor of Philosophy students and postdoctoral participants. Further study is needed to assess the impact of TREKS on enrollment in nephrology fellowship programs.

The times they are K+-changin': bringing the potassium curriculum out of the 20th century.

PURPOSE OF REVIEW: Although most of the current medical education literature has focused on teaching strategies, little attention has been devoted to selecting appropriate course content. Despite elegant descriptions of physiologic mechanisms in recent decades, medical school curricula and students continue to rely on outdated textbooks and certification examination study aids composed to fit an antiquated exam blueprint. RECENT FINDINGS: Advances in our understanding of potassium physiology offer multiple examples of key concepts that deserve to be included in the modern-day renal physiology curriculum, including the relationship of potassium to blood pressure and the potassium 'switch', the aldosterone paradox, and novel pharmacologic agents that target dietary potassium absorption and potassium handling in the kidney. SUMMARY: Key advances in our understanding and application of renal physiology to patient care have not been readily integrated into the nephrology curriculum of medical students. Difficult questions remain regarding when new concepts are sufficiently established to be introduced to medical students in the preclinical years.

The Interdialytic Creatinine Rise is a novel marker of volume overload and mortality risk in hemodialysis patients.

BACKGROUND: Volume overload poses a major risk in hemodialysis patients but simple detection methods are lacking. We propose a novel marker, the Interdialytic Creatinine Rise (IDCR), readily calculated as the change in serum creatinine over time (in mg/dL/h), to assess volume overload and predict mortality risk in hemodialysis patients. METHODS: First, we calculated IDCR changes with volume in a prospective cohort of 35 hospitalized hemodialysis patients awaiting hemodialysis and 33 hospitalized patients undergoing hemodialysis every other day. Second, in a prospective cohort of 25 outpatients, IDCR cutoff values associated with hypervolemia were determined between two treatments and compared with simultaneous volume assessments by their nephrologist. Third, IDCR as a mortality predictor was studied using survival analysis in a longitudinal retrospective cohort study of 39 maintenance hemodialysis patients followed from 2012 until death or 2017. RESULTS: IDCR decreased by - 0.014 mg/dL/h each day (95%CI - 0.017,- 0.010; p < 0.001) without dialysis due to fluid volume gain and increased by 0.013 mg/dL/h (95%CI 0.008,0.017; p < 0.001) from before to after each successive hemodialysis due to fluid removal. Choosing an IDCR cutoff value of ≤0.1 had sensitivity of 82% and specificity of 79% in diagnosing volume overload with the area under the ROC curve of 0.78 (95%CI 0.59,0.97). The hazard ratio of death for each 0.01 decrease in IDCR was 1.64 (95%CI 1.31,2.07; p < 0.001). If IDCR decreased to less than 0.05 mg/dL/h, the median survival was 32 days and the odds ratio of death within 2 months was 38 (95%CI 8, 131; p < 0.001). CONCLUSIONS: In this pilot study, IDCR is shown to be a novel metric that decreases with fluid retention and increases after fluid removal. IDCR can assist clinicians in detection or exclusion of volume overload in hemodialysis patients and provide prognostic value in identifying those at high risk for death.

Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure.

BACKGROUND: Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. METHODS: Systolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. RESULTS: 54 male patients (66.6 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 2.8 relative units, respectively; P ≤ .05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P < .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1ß, and IL-6 were similar in HF and control. CONCLUSION: Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

Myosin light chain phosphorylation is critical for adaptation to cardiac stress.

BACKGROUND: Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. METHODS AND RESULTS: We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. CONCLUSIONS: Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.

Acid Base Disorders in Cirrhosis.

Metabolic and respiratory acid-base disorders are common in individuals with liver disease and cirrhosis. The most common disorder is respiratory alkalosis, which may be related to dyspnea or respiratory stimulation. Primary metabolic disorders are less common. Although the liver plays a role in metabolism of amino acids and generation of acid from dietary sources, it does not play a role in the regulation of pH. Instead, metabolic disorders may arise from alterations in normal metabolism or from medications, particularly diuretics and osmotic laxatives, used in the treatment of these complex patients. Understanding the mechanistic underpinnings of these disorders can aid in the management of individuals with liver disease in the hospital and in outpatient settings.

FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.

Muscle atrophy occurs in many pathological states and results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. However, the importance of lysosomes in muscle atrophy has received little attention. Activation of FoxO transcription factors is essential for the atrophy induced by denervation or fasting, and activated FoxO3 by itself causes marked atrophy of muscles and myotubes. Here, we report that FoxO3 does so by stimulating overall protein degradation and coordinately activating both lysosomal and proteasomal pathways. Surprisingly, in C2C12 myotubes, most of this increased proteolysis is mediated by lysosomes. Activated FoxO3 stimulates lysosomal proteolysis in muscle (and other cell types) by activating autophagy. FoxO3 also induces the expression of many autophagy-related genes, which are induced similarly in mouse muscles atrophying due to denervation or fasting. These studies indicate that decreased IGF-1-PI3K-Akt signaling activates autophagy not only through mTOR but also more slowly by a transcription-dependent mechanism involving FoxO3.

Proteolysis by the ubiquitin-proteasome system and kidney disease.

Proteins in all cells turnover continuously such that rigorous control of proteolysis is required to govern levels of proteins with vastly different half-lives and actions including those regulating transcription, metabolic pathways, or the breakdown of muscle proteins to amino acids used in gluconeogenesis or the synthesis of new proteins. Critical cellular functions would be disrupted without precise regulation of protein degradation. Thus, it is surprising that the bulk of protein in all cells is degraded by the ATP-dependent, ubiquitin-proteasome system. The system achieves remarkable specificity by selective conjugation of ubiquitin (Ub) to a doomed protein in a process catalyzed by >1000 ubiquitin ligases that recognize individual substrate proteins. Because the pathogenesis of certain kidney diseases and their complications are linked to the function of the ubiquitin-proteasome system, understanding its mechanisms could lead to novel therapies.

What's Old Is New Again: Harnessing the Power of Original Experiments to Learn Renal Physiology.

Although medical schools across the United States have updated their curricula to incorporate active learning techniques, there has been little discussion on the nature of the content presented to students. Here, we share detailed examples of our experience in using original experiments to lay the groundwork for foundational concepts in renal physiology and pathophysiology. We believe that this approach offers distinct advantages over standard case-based teaching by (1) starting with simple concepts, (2) analyzing memorable visuals, (3) increasing graphical literacy, (4) translating observations to "rules," (5) encouraging critical thinking, and (6) providing historical perspective to the study of medicine. Although we developed this content for medical students, we have found that many of these lessons are also appropriate as foundational concepts for residents and fellows and serve as an excellent springboard for increasingly complex discussions of clinical applications of physiology. The use of original experiments for teaching and learning in renal physiology harnesses skills in critical thinking and provides a solid foundation that will help learners with subsequent case-based learning in the preclerkship curriculum and in the clinical arena.

More than meets the I(ris): Use of manual urine microscopy to complement automated findings in acute kidney injury.

Evaluation of patients with acute kidney injury requires comprehensive assessment that includes a urinalysis, which features both semi-quantitative assessment with a urine dipstick and urine microscopy. This process is labor intensive for clinical laboratories, and availability of excellent automated instruments for urinalysis has prompted utilization and acceptance of this strategy by both by laboratories and clinicians. Recently, however, interest in provider performed microscopy has enjoyed a renaissance thanks to both improved microscopy techniques and the endorsement from social media in nephrology. Here, we present two cases of acute kidney injury in which manual microscopy added valuable information to the automated microscopy.

Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks.

Improvements in health in the past decades have resulted in increased numbers of the elderly in both developed and developing regions of the world. Advances in therapy have also increased the prevalence of patients with chronic and degenerative diseases. Muscle wasting, a feature of most chronic diseases, is prominent in the elderly and contributes to both morbidity and mortality. A major research goal has been to identify the proteolytic system(s) that is responsible for the degradation of proteins that occurs in muscle atrophy. Findings over the past 20 years have clearly confirmed an important role of the ubiquitin proteasome system in mediating muscle proteolysis, particularly that of myofibrillar proteins. However, recent observations have provided evidence that autophagy, calpains and caspases also contribute to the turnover of muscle proteins in catabolic states, and furthermore, that these diverse proteolytic systems interact with each other at various levels. Importantly, a number of intracellular signaling pathways such as the IGF1/AKT, myostatin/Smad, PGC1, cytokine/NFκB, and AMPK pathways are now known to interact and can regulate some of these proteolytic systems in a coordinated manner. A number of loss of function studies have identified promising therapeutic approaches to the prevention and treatment of wasting. However, additional biomarkers and other approaches to improve early identification of patients who would benefit from such treatment need to be developed. The current data suggests a network of interacting proteolytic and signaling pathways in muscle. Future studies are needed to improve understanding of the nature and control of these interactions and how they work to preserve muscle function under various states of growth and atrophy.

Incidence and risk factors of venous thromboembolism in ANCA-associated vasculitis: a metaanalysis and metaregression.

The incidence of venous thromboembolism (VTE) in ANCA-associated vasculitis patients varies in different populations. Moreover, the risk factors for VTE in these patients are poorly described due to the small number of events. Ovid MEDLINE, EMBASE, and the Cochrane Library were searched for eligible articles. The inclusion criteria included observational studies that enrolled patients age ≥ 18 years diagnosed with ANCA-associated vasculitis. The incidence of VTE is the outcome of interest. Of 1362 citations, a total of 21 studies (n = 4422) dated from 2006 to 2019 were included in the systematic review. The mean age was 54.2 ± 4.0 years. Most were male (52.0%) and Caucasian (80.9%). With a mean follow-up duration of 5.2 ± 2.8 years, the pooled incidence of VTE in ANCA-associated vasculitis patients was 12.4% (95% CI, 8.8-17.2). Of these, 63.4% (95% CI, 57.3-69.1) had deep vein thrombosis and 26.3% (95% CI, 17.6-37.4) had pulmonary embolism. Recurrent VTE occurred in 10.0% (95% CI, 5.2-18.6). From the metaregression adjusted for age, sex, and ethnicity; positive MPO-ANCA, increasing Birmingham Vasculitis Activity Score at time of vasculitis diagnosis, and presence of renal involvement were positively associated with increased VTE events. Positive PR3-ANCA profile was inversely associated with increased VTE events. Increasing follow-up duration was not associated with increased VTE events. VTE in ANCA-associated vasculitis is common. Positive MPO-ANCA, increasing vasculitis activity, and presence of renal involvement were significant risk factors for VTE while positive PR3-ANCA was inversely associated with increased VTE. Key Points • Venous thromboembolism (VTE) is common in ANCA-associated vasculitis with a pooled incidence of 12.4% • Deep vein thrombosis accounts for two-third of total VTE cases • Positive MPO-ANCA profile, higher disease activity at ANCA-associated vasculitis diagnosis, and renal involvement are risk factors for VTE • Positive PR3-ANCA profile is protective factor for VTE.

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity.

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1alpha, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.

Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect.

Statins are widely used to treat hypercholesterolemia but can lead to a number of side effects in muscle, including rhabdomyolysis. Our recent findings implicated the induction of atrogin-1, a gene required for the development of muscle atrophy, in statin-induced muscle damage. Since statins inhibit many biochemical reactions besides cholesterol synthesis, we sought to define the statin-inhibited pathways responsible for atrogin-1 expression and muscle damage. We report here that lovastatin-induced atrogin-1 expression and muscle damage in cultured mouse myotubes and zebrafish can be prevented in the presence of geranylgeranol but not farnesol. Further, inhibitors of the transfer of geranylgeranyl isoprene units to protein targets cause statin muscle damage and atrogin-1 induction in cultured cells and in fish. These findings support the concept that dysfunction of small GTP-binding proteins lead to statin-induced muscle damage since these molecules require modification by geranylgeranyl moieties for their cellular localization and activity. Collectively, our animal and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be regulated by novel signaling pathways.

Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications.

BACKGROUND AND OBJECTIVES: Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a systematic review and meta-analysis of the literature published from January 1983 to March 2018. The initial PubMed search yielded 1139 manuscripts. Using predetermined selection criteria, 87 manuscripts were included in the final analysis. A random effects meta-analysis for proportions was used to obtain combined estimates of complication rates. Freeman-Tukey double-arcsine transformations were used to stabilize variance as complications were rare. RESULTS: A total of 118,064 biopsies were included in this study. Patient age ranged from 30 to 79 years, and 45% of patients were women. On the basis of our meta-analysis, pain at the site of biopsy is estimated to occur in 4.3% of biopsied patients, hematomas are estimated to occur in 11%, macroscopic hematuria is estimated to occur in 3.5%, bleeding requiring blood transfusions is estimated to occur in 1.6%, and interventions to stop bleeding are estimated to occur in only 0.3%. Death attributed to native kidney biopsy was a rare event, occurring only in an estimated 0.06% of all biopsies but only 0.03% of outpatient biopsies. Complication rates were higher in hospitalized patients and in those with acute kidney disease. The reported complications varied on the basis of study type and geographic location. CONCLUSIONS: Although the native kidney biopsy is an invasive diagnostic procedure, the rates of bleeding complications are low. Albeit rare, death can occur postbiopsy. Complications are more frequently seen after kidney biopsies of hospitalized patients with AKI.

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.

Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases.

We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states (fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 (35- to 44-fold) and MuRF1 (12- to 22-fold), and the suppression of PGC-1alpha and PGC-1beta coactivators (15-fold). When atrophy slowed (day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.