The Impact of Internal Medicine Clerkship Characteristics and NBME Subject Exams on USMLE Step 2 Clinical Knowledge Exam Performance.

BACKGROUND: Residency program directors will likely emphasize the United States Medical Licensing Exam (USMLE) Step 2 clinical knowledge (CK) exam more during residency application given the recent USMLE Step 1 transition to pass/fail scoring. We examined how internal medicine clerkship characteristics and NBME subject exam scores affect USMLE Step 2 CK performance. DESIGN: The authors used univariable and multivariable generalized estimating equations to determine associations between Step 2 CK performance and internal medicine clerkship characteristics and NBME subject exams. The sample had 21,280 examinees' first Step 2 CK scores for analysis. RESULTS: On multivariable analysis, Step 1 performance (standardized ß = 0.45, p < .001) and NBME medicine subject exam performance (standardized ß = 0.40, p < .001) accounted for approximately 60% of the variance in Step 2 CK performance. Students who completed the internal medicine clerkship last in the academic year scored lower on Step 2 CK (Mdiff = -3.17 p < .001). Students who had a criterion score for passing the NBME medicine subject exam scored higher on Step 2 CK (Mdiff = 1.10, p = .03). There was no association between Step 2 CK performance and other internal medicine clerkship characteristics (all p > 0.05) nor with the total NBME subject exams completed (ß=0.05, p = .78). CONCLUSION: Despite similarities between NBME subject exams and Step 2 CK, the authors did not identify improved Step 2 CK performance for students who had more NBME subject exams. The lack of association of Step 2 CK performance with many internal medicine clerkship characteristics and more NBME subject exams has implications for future clerkship structure and summative assessment. The improved Step 2 CK performance in students that completed their internal medicine clerkship earlier warrants further study given the anticipated increase in emphasis on Step 2 CK.

Medical Student Experience and Outcomes, as Well as Preceptor Experience, with Rapid Conversion of a Preclinical Medical School Course to a Remote-Based Learning Format in the Setting of the COVID-19 Pandemic.

OBJECTIVES: To assess student outcomes and experiences, as well as preceptor experiences, after emergently converting a preclinical medical school renal course to a remote setting during the COVID-19 pandemic. METHODS: First-year medical student examination scores and responses to Likert-scale questions on end-of-course evaluations from the 2018-2019 (traditional) and 2019-2020 (remote) academic years were compared. Free-text responses from students and preceptors were analyzed using a qualitative summative approach to extract major themes in perceptions of remote learning. RESULTS: Mean student scores on course examinations did not significantly differ between the traditional and remote settings (p = 0.23 and 0.84 respectively). Quantitative analysis of student evaluations revealed no significant difference across all items in mean Likert-scale responses. Student and preceptor free-text responses identified course leader engagement and responsiveness as essential to the success of remote-based learning. Optimal group size and online etiquette are areas that require attention. CONCLUSIONS: Despite rapid conversion of a preclinical medical school renal course to a remote-based format in the setting of the COVID-19 pandemic, student scores and evaluations remain positive and largely unchanged.

Medical Student Personality Traits and Clinical Grades in the Internal Medicine Clerkship.

BACKGROUND: Third year clerkship grades include subjective evaluations. The purpose of this study is to identify if personality traits and self-esteem predispose students to better clerkship performance. METHODS: Third-year medical students completed the OCEAN Five Factor Model Personality Test and Rosenberg Self-Esteem Scale. Clerkship grades were matched to survey results. Chi-squared and linear regression analyses assessed the correlation between students' clerkship grades, personality traits, and self-esteem. RESULTS: There was no association between OCEAN personality domains and any component of clerkship grade. In secondary post hoc analysis, students who are "deep thinking" (OR 2.97, 95% CI 1.26-7.01, p = 0.01), "sophisticated" (OR 2.70, 95% CI 1.12-6.50, p = 0.03), and "outgoing" (OR 2.45, 95% CI 1.02-5.89, p = 0.04) were significantly more likely to get an overall clerkship grade of Honors. "Deep thinking" (OR 3.44, 95% CI 1.47-8.04, p = 0.004) and "efficient" (OR 2.87, 95% CI 1.12-7.36, p = 0.03) students scored better on shelf exams, while "shy" students scored worse (OR 0.30, 95% CI 0.13-0.69, p = 0.004); "aloof" students received worse clinical scores (OR 0.57, 95% CI 0.37-0.89, p = 0.03), and "rude" (OR 5.08, 95% CI 1.03-24.94, p = 0.03) and "sophisticated" (OR 2.47, 95% CI 1.02-6.00, p = 0.04) students received higher preceptor scores. There was no correlation between self-esteem and clerkship grades. CONCLUSION: Students with certain personality traits may be predisposed to success during clerkships. Medical educators should be cognizant of biases favoring certain personalities and help students maximize success by recognizing their strengths and identifying gaps.

Medical student remote eConsult participation during the COVID-19 pandemic.

BACKGROUND: Undergraduate medical education was severely impacted by the COVID-19 pandemic. As traditional clinical rotations were suspended, medical students quickly began alternative, novel educational experiences. Third-year medical students at an academic medical center were given the opportunity to join inpatient eConsult teams within the department of medicine. This study describes the development and implementation of this program as well as the experiences of student and faculty participants. METHODS: Student eConsult participation was rapidly developed and implemented within medical subspecialty teams in either infectious diseases (ID) or nephrology. Twelve third-year medical students and 15 subspecialty attendings participated in this program during an eight-week period from April 6 through May 29, 2020. Breadth of student clinical experience was assessed via review of clinical documentation and surveys. Participating students and attending physicians completed surveys to reflect upon their impressions of the program. Surveys were returned by nine students and eight faculty members. Survey responses were summarized with descriptive statistics. RESULTS: Over an eight-week period, student consultants wrote 126 notes on 100 patients; 74 of these patients (74%) were hospitalized with COVID-19. Student experiences were largely positive with most strongly agreeing that attendings promoted interactive and engaged learning (N = 8 of 8, 100%), that the experience helped to expand their knowledge about consultant roles (N = 6, 75%), and that they would participate in a remote eConsult program again if given the opportunity (N = 6, 75%). Faculty also were largely positive about the experience with most agreeing or strongly agreeing with the importance of teaching medical students about telehealth (N = 7 of 8, 88%) and eConsults (N = 6, 75%). In narrative responses, students and faculty agreed that teaching was a strength of the program whereas lack of in-person contact was a challenge. CONCLUSIONS: Rapid development of an inpatient eConsult-based educational experience for third-year medical students was feasible and successful. Student-consultants saw a range of pathology including COVID-19 and related complications. Students were satisfied with the program. They were able to develop a strong relationship with attendings while learning about the role of a consultant. Faculty agreed with the importance of teaching students about telehealth and eConsults specifically.

Great nephrologists begin with great teachers: update on the nephrology curriculum.

PURPOSE OF REVIEW: The purpose of this review is to highlight developments and opportunities in the nephrology curriculum from the basic science foundation years through teaching medical students, residents and fellows in the clinical realm. RECENT FINDINGS: Teaching skills are a vital tool for nephrologists both to promote excellent patient care and attract talented learners to the field. Exposure to dynamic and inspiring nephrologists is one of the main factors given by students and residents for selecting a career in nephrology. Nephrology teaching, including case discussions, problem-based learning, team-based learning and flipped classrooms, provides motivating active learning for medical students and is equally effective for didactics in graduate medical education. Avenues for teaching in the clinical realm include the microskills framework, bedside teaching and grounding in evidence-based medicine. Areas of growth include blended nephrology/subspecialty fields as well as social media applications. SUMMARY: Medical education is a satisfying and exciting area of growth in the field of nephrology. The recent literature provides a framework for best practices in active learning as well as providing numerous examples of educational interventions and innovations. In addition, this field is ripe for further development and scholarly activity.

Which Internal Medicine Clerkship Characteristics Are Associated With Students' Performance on the NBME Medicine Subject Exam? A Multi-Institutional Analysis.

PURPOSE: To identify which internal medicine clerkship characteristics may relate to NBME Medicine Subject Examination scores, given the growing trend toward earlier clerkship start dates. METHOD: The authors used linear mixed effects models (univariable and multivariable) to determine associations between medicine exam performance and clerkship characteristics (longitudinal status, clerkship length, academic start month, ambulatory clinical experience, presence of a study day, involvement in a combined clerkship, preclinical curriculum type, medicine exam timing). Additional covariates included number of NBME clinical subject exams used, number of didactic hours, use of a criterion score for passing the medicine exam, whether medicine exam performance was used to designate clerkship honors, and United States Medical Licensing Examination Step 1 performance. The sample included 24,542 examinees from 62 medical schools spanning 3 academic years (2011-2014). RESULTS: The multivariable analysis found no significant association between clerkship length and medicine exam performance (all pairwise P > .05). However, a small number of examinees beginning their academic term in January scored marginally lower than those starting in July (P < .001). Conversely, examinees scored higher on the medicine exam later in the academic year (all pairwise P < .001). Examinees from schools that used a criterion score for passing the medicine exam also scored higher than those at schools that did not (P < .05). Step 1 performance remained positively associated with medicine exam performance even after controlling for all other variables in the model (P < .001). CONCLUSIONS: In this sample, the authors found no association between many clerkship variables and medicine exam performance. Instead, Step 1 performance was the most powerful predictor of medicine exam performance. These findings suggest that medicine exam performance reflects the overall medical knowledge students accrue during their education rather than any specific internal medicine clerkship characteristics.

Group observed structured encounter (GOSCE) for third-year medical students improves self-assessment of clinical communication.

OBJECTIVES: This study assesses the effectiveness of a GOSCE in teaching medical students clinical communication, as well as group collaboration and peer feedback. METHODS: The GOSCE was administered during the Internal Medicine clerkship. Groups consisted of 4-6 students and one faculty member. Students completed pre- and post-GOSCE surveys to assess confidence in clinical communication and a GOSCE evaluation to rate the overall experience. Pre- and post-GOSCE program survey scores were compared, and the mean score and standard deviation of the GOSCE evaluation was calculated. RESULTS: Students perceived improvement in their general (Mean 4.49-4.57, p < .0001), case-specific (3.61-3.84, p < .0001) and group clinical communication (3.75-4.09, p < .0001) skills. Students agreed or strongly agreed that the GOSCE taught them something new (91.20%), made them more comfortable in giving (64.31%) and receiving (66.57%) feedback and working with a group (64.22%). Students found the GOSCE to be as effective as an OSCE (70.97%). CONCLUSIONS: A GOSCE is a valuable resource for use in formative assessment of clinical communication, and it offers the benefit of group collaboration and peer feedback. These findings support the broader use of GOSCEs in undergraduate medical education.

Improving the diagnostic workup of hyponatremia in the setting of kidney disease: a continuing medical education (CME) initiative.

PURPOSE: Hyponatremia is a common electrolyte disorder and is associated with mortality. We examined the frequency of appropriate testing in response to an episode of inpatient hyponatremia in a large urban hospital to better inform our educational intervention. We then evaluated the impact of a live CME activity with a focus on CKD- and ESRD-associated hyponatremia physiology, on diagnostic practices of audience hospitalist attendings. METHODS: We performed a retrospective database analysis of all patients admitted to Montefiore Medical Center in 2014 to examine the performance of hospital staff in response to hyponatremia across all CKD stages. We then did a comparative analysis of diagnostic workup orders for hyponatremic patients admitted to audience members of a live CME activity in the 4 months prior as compared to the 4 months after the activity. RESULTS: The prevalence of hyponatremia was 27% in a cohort of hospitalized patients: 41% of these hyponatremia inpatients had CKD, and 11.4% had ESRD. Overall less than 10% of patients had orders written for serum and urine osmolality without a differential pattern based on CKD or ESRD diagnosis. Among the patients admitted to the CME audience hospitalists, urine/serum osmolality and urine sodium orders occurred infrequently overall and did not differ after vs. before the lecture. DISCUSSION: The frequency of appropriate diagnostic orders written in response to an episode of hyponatremia was very low and did not vary based on degree of CKD. A CME activity with an emphasis on the role of CKD/ESRD in diagnostic accuracy did not improve the order quality in a group of audience hospitalists. Efforts to improve the diagnostic workup of hyponatremia with concomitant kidney disease are crucial to proper management of these patients.

Effect of oral sodium bicarbonate on fibroblast growth factor-23 in patients with chronic kidney disease: a pilot study.

BACKGROUND: The regulation of fibroblast growth factor-23 (FGF23) secretion in patients with chronic kidney disease (CKD) is incompletely understood. An in vitro study showed that metabolic acidosis increased FGF23 in mouse bone. The objective of this study is to evaluate the effect of oral sodium bicarbonate on circulating FGF23 levels in patients with CKD. METHODS: This was a single-blind pilot study. Twenty adults with estimated glomerular filtration rate between 15-45 mL/min/1.73 m(2) and serum bicarbonate between 20-24 mEq/L were treated with placebo for 2 weeks, followed by increasing doses of oral sodium bicarbonate (0.3, 0.6 and 1.0 mEq/kg/day) in 2 week intervals for a total of 6 weeks. C-terminal FGF23 levels were measured at the initial visit, after 2 weeks of placebo and after 6 weeks of bicarbonate therapy. Wilcoxon matched-pairs signed-rank test was used to compare FGF23 before and after sodium bicarbonate. RESULTS: After 6 weeks of oral sodium bicarbonate, the median FGF23 increased significantly from 150.9 RU/mL (IQR 107.7-267.43) to 191.4 RU/mL (IQR 132.6-316.9) (p = 0.048) and this persisted after excluding participants who received activated vitamin D. CONCLUSIONS: FGF23 increased after short-term oral sodium bicarbonate therapy in patients with CKD and mild metabolic acidosis. It is unclear whether this was due to the alkalinizing effect of sodium bicarbonate or other factors. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT00888290 ) on April 23, 2009.

Four-Station Group Observed Structured Clinical Encounter for Formative Assessment of Communication Skills for Internal Medicine Clerks.

INTRODUCTION: Communication with patients and among colleagues is critical to effective clinical care. A group observed structured clinical encounter (GOSCE) is an effective and resource-saving tool for teaching communication skills to medical students. While objective structured clinical exams (OSCEs) are a well-established assessment tool for communication skills, a GOSCE allows for formal observation of communication skills while also providing an opportunity for peer observation and feedback. Additionally, a GOSCE costs less and requires fewer faculty per learner than a traditional OSCE. METHODS: This is a four-station GOSCE to teach advanced communication skills to medical students. The stations are smoking cessation, difficult doctor-patient encounter, shared decision making, and delivering bad news. A group is made up of four to six students and one faculty member. At each station, one student takes the lead in the patient interview, followed by a group interview and ending with feedback by all participants. RESULTS: In the pilot phase, a total of 44 students were administered the GOSCE and were surveyed about their experience. Students felt the GOSCE was an enjoyable and educational experience. The GOSCE has subsequently been administered to more than 600 students, and 25 internal medicine faculty have participated. DISCUSSION: Our work demonstrates that the GOSCE is a feasible curricular enhancement for formative assessment of communication skills during the internal medicine clerkship. It is easy to implement and has been well received by all participants, with minimal impact on limited medical school and faculty resources.

A zebrafish model for uremic toxicity: role of the complement pathway.

Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

Effects of oral sodium bicarbonate in patients with CKD.

BACKGROUND AND OBJECTIVES: Metabolic acidosis contributes to muscle breakdown in patients with CKD, but whether its treatment improves functional outcomes is unknown. The choice of dose and tolerability of high doses remain unclear. In CKD patients with mild acidosis, this study evaluated the dose-response relationship of alkali with serum bicarbonate, its side effect profile, and its effect on muscle strength. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this single-blinded pilot study from March of 2009 to August of 2010, 20 adults with estimated GFR 15-45 ml/min per 1.73 m(2) and serum bicarbonate 20-24 mEq/L were treated during successive 2-week periods with placebo followed by escalating oral NaHCO3 doses (0.3, 0.6, and 1.0 mEq/kg per day). At each visit, handgrip strength and time required to complete 5 and 10 repetitions of a sit-to-stand test were measured. RESULTS: Each 0.1 mEq/kg per day increase in dose produced a 0.33 mEq/L (95% confidence interval=0.23-0.43 mEq/L) higher serum bicarbonate. Sit-to-stand time improved after 6 weeks of oral NaHCO3 (23.8±1.4 versus 22.2±1.6 seconds for 10 repetitions, P=0.002), and urinary nitrogen excretion decreased (-0.70 g/g creatinine [95% confidence interval=-1.11 to -0.30] per 0.1 mEq/kg per day higher dose). No statistically significant change was seen in handgrip strength (29.5±9.6 versus 28.4±9.4 kg, P=0.12). Higher NaHCO3 doses were not associated with increased BP or greater edema. CONCLUSIONS: NaHCO3 supplementation produces a dose-dependent increase in serum bicarbonate and improves lower extremity muscle strength after a short-term intervention in CKD patients with mild acidosis. Long-term studies are needed to determine if this finding translates into improved functional status.

Olfactory function in dialysis patients: a potential key to understanding the uremic state.

Impaired olfactory function is a marker of neurologic dysfunction in the uremic state. Retained uremic toxins not adequately cleared with dialysis may undermine the integrity of the olfactory epithelium and olfactory bulb and malign central olfactory processing. The evidence suggests that only renal transplantation, with its concomitant thorough reversal of uremia, truly restores olfactory function to normal in end-stage renal disease. Testing of olfactory function may emerge as an important marker for the extent and resolution of uremia.

Methylamine clearance by haemodialysis is low.

BACKGROUND: Dialysis adequacy is currently judged by measures of urea clearance. However, urea is relatively non-toxic and has properties distinct from large classes of other retained solutes. In particular, intracellularly sequestered solutes are likely to behave differently than urea. METHODS: We studied an example of this class, the aliphatic amine monomethylamine (MMA), in stable haemodialysis outpatients (n = 10) using an HPLC-based assay. RESULTS: Mean MMA levels pre-dialysis in end-stage renal disease subjects were 76 +/- 15 microg/L compared to 32 +/- 4 microg/L in normal subjects (n = 10) (P < 0.001). Mean urea reduction was 62% while the reduction ratio for MMA was 43% (P < 0.01). MMA levels rebounded in the 1 hour post-dialytic period to 85% of baseline, whereas urea levels rebounded only to 47% of baseline. MMA had a much larger calculated volume of distribution compared to urea, consistent with intracellular sequestration. Measures of intra-red blood cell (RBC) MMA concentrations confirmed greater levels in RBCs than in plasma with a ratio of 4.9:1. Because of the intracellular sequestration of MMA, we calculated its clearance using that amount removed from whole blood. Clearances for urea averaged 222 +/- 41 ml/min and for MMA 121 +/- 14 ml/min, while plasma clearance for creatinine was 162 +/- 20 ml/min (P < 0.01, for all differences). Using in vitro dialysis, in the absence of RBCs, solute clearance rates were similar: 333 +/- 6, 313 +/- 8 and 326 +/- 4 ml/min for urea, creatinine and MMA, respectively. These findings suggest that the lower MMA clearance relative to creatinine in vivo is a result of MMA movement into RBCs within the dialyser blood path diminishing its removal by dialysis. CONCLUSION: In conclusion, we find that, in conventional haemodialysis, MMA is not cleared as efficiently as urea or creatinine and raise the possibility that RBCs may limit its dialysis not merely by failing to discharge it, but by further sequestering it as blood passes through the dialyser.

New insights into uremic toxicity.

PURPOSE OF REVIEW: Our concept of uremia has expanded to encompass the illness patients begin to suffer as glomerular filtration rate declines long before the onset of end-stage renal disease (ESRD) not explained by known derangements in volume status or metabolic parameters. New insights into the accumulation of uremic toxins and the loss of function of hormones and enzymes provide important information on the etiology of uremia. RECENT FINDINGS: New data are accumulating on the identity and toxicity of uremic toxins and the syndromes that encompass uremia. rho-Cresol sulfate and indoxyl sulfate are small, protein-bound molecules that are poorly cleared with dialysis. These molecules have been linked to cardiovascular disease and oxidative injury. Impaired immunity plays a central role in the morbidity of ESRD and may be both the result of uremic toxicity and a contributor to oxidative stress in ESRD. Uremic cachexia is an underrecognized uremic syndrome. New insights into disordered feeding circuits in ESRD may lead to novel therapies using hormone agonists. SUMMARY: Mortality in ESRD remains unacceptably high. It is hoped that as knowledge emerges on the causes and consequences of uremia, we are embarking on an era not only of new insights but also new and effective treatments for patients with the ill effects of uremia.

Relationship of impaired olfactory function in ESRD to malnutrition and retained uremic molecules.

BACKGROUND: Olfactory function is impaired in patients with end-stage renal disease (ESRD) and may contribute to uremic anorexia. Only limited correlations of olfactory function and nutritional status were reported. This study examines the relationship of impaired olfactory function to malnutrition and levels of the retained uremic solutes monomethylamine, ethylamine, indoxyl sulfate, and P-cresol sulfate. STUDY DESIGN: Cross-sectional observational study. SETTING & PARTICIPANTS: 31 stable maintenance hemodialysis patients from an urban outpatient dialysis unit and 18 people with normal renal function participated. PREDICTOR: Nutritional status assigned by using Subjective Global Assessment (SGA) score; SGA score of 7 indicates normal nutritional status; SGA score of 5 to 6, mild malnutrition; and SGA score of 3 to 4, moderate malnutrition. OUTCOMES & MEASUREMENTS: The primary outcome is olfactory function, assessed using the University of Pennsylvania Smell Identification Test. Levels of retained uremic solutes were measured from a predialysis serum sample. Demographic data and laboratory values for nutritional status, adequacy of dialysis, and inflammation were collected. RESULTS: Mean smell scores were 34.9 +/- 1.4 for controls, 33.5 +/- 3.3 for patients with SGA score of 7, 28.3 +/- 5.8 for patients with SGA score of 5 to 6, and 27.9 +/- 4.4 for patients with SGA score of 3 to 4 (P < 0.001 comparing healthy patients with all patients with ESRD). There was no difference in mean smell scores for healthy controls and patients with SGA score of 7. However, patients with lower smell scores had significantly lower SGA scores (P = 0.02) and higher C-reactive protein levels (P = 0.02). Neither smell score nor nutritional status was associated with levels of retained uremic solutes. LIMITATIONS: Small sample size, only cross-sectional associations can be described. CONCLUSIONS: Our results suggest an association between poor nutritional status and impaired olfactory function in patients with ESRD. Additional research is needed to discover the uremic toxins mediating these processes.

Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyperglycemia in Ins2(Akita) (Akita) mice with type 1 diabetes and Lepr(db/db) (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37% reduction) and db/db (27% reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular reactive oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapoptotic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apoptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic nephropathy in murine type 1 and type 2 diabetic models.

Localization of the GLUT8 glucose transporter in murine kidney and regulation in vivo in nondiabetic and diabetic conditions.

Kidney disease is a major complication of diabetes, and poor glycemic control is associated with the development of diabetic nephropathy. The precise mechanisms that lead to diabetic kidney disease still remain largely unknown and are under current investigation. Because glucose transporters in the kidney play an important role in the local maintenance of intracellular glucose and plasma glucose homeostasis, the tissue distribution and regulation of glucose transporter GLUT8, a new member of the glucose transporter family with important functions in cellular survival, were examined. To understand the normal regulation of GLUT8 expression in response to metabolic signals, fasting and feeding conditions were studied. Additionally, GLUT8 expression was studied using two different models of insulin resistance, GLUT4-/- and db/db mice. GLUT8 was localized to glomerular podocytes and tubular epithelial cells in the distal portion of the nephron. Expression of GLUT8 in the kidney was influenced by plasma glucose levels in vivo. Podocytes in kidneys of diabetic db/db mice express higher levels of GLUT8 compared with nondiabetic db/m mice. Because podocytes play an important role in glomerulosclerosis development and high levels of glucose have been shown to induce apoptotic cell death in various kidney cells, these data may provide further insight into the pathogenesis of glomerulosclerosis and diabetic nephropathy.